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Parkinson Disease: HELP
Articles by Rubén Fernández-Santiago
Based on 27 articles published since 2010
(Why 27 articles?)
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Between 2010 and 2020, R. Fernández-Santiago wrote the following 27 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Parkinson's disease as a systemic pathology. 2019

Ezquerra, Mario / Martí, María-José / Fernández-Santiago, Rubén. ·Laboratory of Neurodegenerative Disorders, Department of Neurology-Hospital Clínic of Barcelona, IDIBAPS, UB, 08036 Barcelona, Catalonia. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain. ·Aging (Albany NY) · Pubmed #30745469.

ABSTRACT: -- No abstract --

2 Review Advances in Parkinson's Disease: 200 Years Later. 2018

Del Rey, Natalia López-González / Quiroga-Varela, Ana / Garbayo, Elisa / Carballo-Carbajal, Iria / Fernández-Santiago, Rubén / Monje, Mariana H G / Trigo-Damas, Inés / Blanco-Prieto, María J / Blesa, Javier. ·HM CINAC, Hospital Universitario HM Puerta del Sur, Madrid, Spain. · Biomedical Research Networking Center on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. · Department of Neuroscience, Centro de Investigación Médica Aplicada (CIMA), University of Navarra, Pamplona, Spain. · Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain. · Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain. · Laboratory of Parkinson Disease and other Neurodegenerative Movement Disorders, Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. · Department of Anatomy, Histology and Neuroscience, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, Spain. ·Front Neuroanat · Pubmed #30618654.

ABSTRACT: When James Parkinson described the classical symptoms of the disease he could hardly foresee the evolution of our understanding over the next two hundred years. Nowadays, Parkinson's disease is considered a complex multifactorial disease in which genetic factors, either causative or susceptibility variants, unknown environmental cues, and the potential interaction of both could ultimately trigger the pathology. Noteworthy advances have been made in different fields from the clinical phenotype to the decoding of some potential neuropathological features, among which are the fields of genetics, drug discovery or biomaterials for drug delivery, which, though recent in origin, have evolved swiftly to become the basis of research into the disease today. In this review, we highlight some of the key advances in the field over the past two centuries and discuss the current challenges focusing on exciting new research developments likely to come in the next few years. Also, the importance of pre-motor symptoms and early diagnosis in the search for more effective therapeutic options is discussed.

3 Review Angiogenin variants in Parkinson disease and amyotrophic lateral sclerosis. 2011

van Es, Michael A / Schelhaas, Helenius J / van Vught, Paul W J / Ticozzi, Nicola / Andersen, Peter M / Groen, Ewout J N / Schulte, Claudia / Blauw, Hylke M / Koppers, Max / Diekstra, Frank P / Fumoto, Katsumi / LeClerc, Ashley Lyn / Keagle, Pamela / Bloem, Bastiaan R / Scheffer, Hans / van Nuenen, Bart F L / van Blitterswijk, Marka / van Rheenen, Wouter / Wills, Anne-Marie / Lowe, Patrick P / Hu, Guo-fu / Yu, Wenhao / Kishikawa, Hiroko / Wu, David / Folkerth, Rebecca D / Mariani, Claudio / Goldwurm, Stefano / Pezzoli, Gianni / Van Damme, Philip / Lemmens, Robin / Dahlberg, Caroline / Birve, Anna / Fernández-Santiago, Rubén / Waibel, Stefan / Klein, Christine / Weber, Markus / van der Kooi, Anneke J / de Visser, Marianne / Verbaan, Dagmar / van Hilten, Jacobus J / Heutink, Peter / Hennekam, Eric A M / Cuppen, Edwin / Berg, Daniela / Brown, Robert H / Silani, Vincenzo / Gasser, Thomas / Ludolph, Albert C / Robberecht, Wim / Ophoff, Roel A / Veldink, Jan H / Pasterkamp, R Jeroen / de Bakker, Paul I W / Landers, John E / van de Warrenburg, Bart P / van den Berg, Leonard H. ·Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, The Netherlands. ·Ann Neurol · Pubmed #22190368.

ABSTRACT: OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 × 10(-6) for ALS and p = 4.3 × 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD.

4 Article The Genetic Architecture of Parkinson Disease in Spain: Characterizing Population-Specific Risk, Differential Haplotype Structures, and Providing Etiologic Insight. 2019

Bandres-Ciga, Sara / Ahmed, Sarah / Sabir, Marya S / Blauwendraat, Cornelis / Adarmes-Gómez, Astrid D / Bernal-Bernal, Inmaculada / Bonilla-Toribio, Marta / Buiza-Rueda, Dolores / Carrillo, Fátima / Carrión-Claro, Mario / Gómez-Garre, Pilar / Jesús, Silvia / Labrador-Espinosa, Miguel A / Macias, Daniel / Méndez-Del-Barrio, Carlota / Periñán-Tocino, Teresa / Tejera-Parrado, Cristina / Vargas-González, Laura / Diez-Fairen, Monica / Alvarez, Ignacio / Tartari, Juan Pablo / Buongiorno, Mariateresa / Aguilar, Miquel / Gorostidi, Ana / Bergareche, Jesús Alberto / Mondragon, Elisabet / Vinagre-Aragon, Ana / Croitoru, Ioana / Ruiz-Martínez, Javier / Dols-Icardo, Oriol / Kulisevsky, Jaime / Marín-Lahoz, Juan / Pagonabarraga, Javier / Pascual-Sedano, Berta / Ezquerra, Mario / Cámara, Ana / Compta, Yaroslau / Fernández, Manel / Fernández-Santiago, Rubén / Muñoz, Esteban / Tolosa, Eduard / Valldeoriola, Francesc / Gonzalez-Aramburu, Isabel / Sanchez Rodriguez, Antonio / Sierra, María / Menéndez-González, Manuel / Blazquez, Marta / Garcia, Ciara / Suarez-San Martin, Esther / García-Ruiz, Pedro / Martínez-Castrillo, Juan Carlos / Vela-Desojo, Lydia / Ruz, Clara / Barrero, Francisco Javier / Escamilla-Sevilla, Francisco / Mínguez-Castellanos, Adolfo / Cerdan, Debora / Tabernero, Cesar / Gomez Heredia, Maria Jose / Perez Errazquin, Francisco / Romero-Acebal, Manolo / Feliz, Cici / Lopez-Sendon, Jose Luis / Mata, Marina / Martínez Torres, Irene / Kim, Jonggeol Jeffrey / Dalgard, Clifton L / Anonymous1451065 / Brooks, Janet / Saez-Atienzar, Sara / Gibbs, J Raphael / Jorda, Rafael / Botia, Juan A / Bonet-Ponce, Luis / Morrison, Karen E / Clarke, Carl / Tan, Manuela / Morris, Huw / Edsall, Connor / Hernandez, Dena / Simon-Sanchez, Javier / Nalls, Mike A / Scholz, Sonja W / Jimenez-Escrig, Adriano / Duarte, Jacinto / Vives, Francisco / Duran, Raquel / Hoenicka, Janet / Alvarez, Victoria / Infante, Jon / Marti, Maria José / Clarimón, Jordi / López de Munain, Adolfo / Pastor, Pau / Mir, Pablo / Singleton, Andrew / Anonymous1461065. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Granada, Spain. · Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA. · Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Seville, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain. · Fundació Docència i Recerca Mútua de Terrassa and Movement Disorders Unit, Department of Neurology, University Hospital Mútua de Terrassa, Terrassa, Barcelona, Spain. · Neurodegenerative Disorders Area, Biodonostia Health Research Institute, San Sebastián, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Plataforma de Genomica, Instituto de Investigacion Biodonostia, San Sebastián, Spain. · Unidad de Trastornos de Movimiento, Departamento de Neurologia, Hospital Universitario de Donostia, San Sebastián, Spain. · Genetics of Neurodegenerative Disorders Unit, IIB Sant Pau, and Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Movement Disorders Unit, Neurology Department, Sant Pau Hospital, Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain. · Lab. of Parkinson disease and Other Neurodegenerative Movement Disorders, IDIBAPS-Institut d'Investigacions Biomèdiques, Barcelona, Catalonia, Spain. · Unitat de Parkinson i Trastorns del Moviment. Servicio de Neurologia, Hospital Clínic de Barcelona and Institut de Neurociencies de la Universitat de Barcelona (Maria de Maetzu Center), Catalonia, Spain. · Servicio de Neurología, Hospital Universitario Marqués de Valdecilla (IDIVAL) and Universidad de Cantabria, Santander, Spain. · Servicio de Neurología, Hospital Universitario Central de Asturias, Asturias, Spain. · Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Asturias, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Madrid, Spain. · Departamento de Neurologia, Instituto Ramón y Cajal de Investigación Sanitaria, Hospital Universitario Ramón y Cajal, Madrid, Spain. · Servicio de Neurologia, Hospital Universitario Fundación Alcorcón, Madrid, Spain. · Centro de Investigacion Biomedica and Departamento de Fisiologia, Facultad de Medicina, Universidad de Granada, Granada, Spain. · Servicio de Neurología, Hospital Universitario San Cecilio, Granada, Universidad de Granada, Spain. · Servicio de Neurología, Hospital Universitario Virgen de las Nieves, Granada, Spain. · Servicio de Neurología, Hospital General de Segovia, Segovia, Spain. · Servicio de Neurología, Hospital Universitario Virgen de la Victoria, Malaga, Spain. · Departamento de Neurologia, Hospital Universitario Infanta Sofía, Madrid, Spain. · Departamento de Neurologia, Instituto de Investigación Sanitaria La Fe, Hospital Universitario y Politécnico La Fe, Valencia, Spain. · Department of Anatomy, Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · The American Genome Center, Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA. · Neuromuscular Diseases Research Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Computational Biology Group, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Murcia, Spain. · Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom. · Department of Neurology, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. · University of Birmingham, Birmingham, United Kingdom. · Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, United Kingdom. · Department of Clinical Neuroscience, University College London, London, United Kingdom. · Department for Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, and DZNE, German Center for Neurodegenerative Diseases, Tübingen, Germany. · Data Tecnica International, Glen Echo, Maryland, USA. · Department of Neurology, Johns Hopkins Medical Center, Baltimore, Maryland, USA. · Laboratorio de Neurogenética y Medicina Molecular, Institut de Recerca Sant Joan de Déu, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Madrid, Spain. · Laboratorio de Genética, Hospital Universitario Central de Asturias, Asturias, Spain. · Departamento de Neurociencias. UPV-EHU, Servicio de Neurología, Hospital Universitario Donostia, San Sebastián, Spain. ·Mov Disord · Pubmed #31660654.

ABSTRACT: BACKGROUND: The Iberian Peninsula stands out as having variable levels of population admixture and isolation, making Spain an interesting setting for studying the genetic architecture of neurodegenerative diseases. OBJECTIVES: To perform the largest PD genome-wide association study restricted to a single country. METHODS: We performed a GWAS for both risk of PD and age at onset in 7,849 Spanish individuals. Further analyses included population-specific risk haplotype assessments, polygenic risk scoring through machine learning, Mendelian randomization of expression, and methylation data to gain insight into disease-associated loci, heritability estimates, genetic correlations, and burden analyses. RESULTS: We identified a novel population-specific genome-wide association study signal at PARK2 associated with age at onset, which was likely dependent on the c.155delA mutation. We replicated four genome-wide independent signals associated with PD risk, including SNCA, LRRK2, KANSL1/MAPT, and HLA-DQB1. A significant trend for smaller risk haplotypes at known loci was found compared to similar studies of non-Spanish origin. Seventeen PD-related genes showed functional consequence by two-sample Mendelian randomization in expression and methylation data sets. Long runs of homozygosity at 28 known genes/loci were found to be enriched in cases versus controls. CONCLUSIONS: Our data demonstrate the utility of the Spanish risk haplotype substructure for future fine-mapping efforts, showing how leveraging unique and diverse population histories can benefit genetic studies of complex diseases. The present study points to PARK2 as a major hallmark of PD etiology in Spain. © 2019 International Parkinson and Movement Disorder Society.

5 Article Accumulation of mitochondrial 7S DNA in idiopathic and LRRK2 associated Parkinson's disease. 2019

Podlesniy, Petar / Puigròs, Margalida / Serra, Núria / Fernández-Santiago, Rubén / Ezquerra, Mario / Tolosa, Eduardo / Trullas, Ramon. ·Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. Electronic address: petar.podlesniy@iibb.csic.es. · Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurology Service, Parkinson's Disease and Movement Disorders Unit, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurobiology Unit, Institut d'Investigacions Biomèdiques de Barcelona, Consejo Superior de Investigaciones Científicas (CSIC), Spain; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. Electronic address: ramon.trullas@iibb.csic.es. ·EBioMedicine · Pubmed #31631040.

ABSTRACT: BACKGROUND: Both idiopathic and familial Parkinson's disease are associated with mitochondrial dysfunction. Mitochondria have their own mitochondrial DNA (mtDNA) and previous studies have reported that the release of mtDNA is a biomarker of Parkinson's disease. METHODS: We have now investigated the relationship between mtDNA replication, transcription and release in fibroblasts from patients with idiopathic (iPD) and Leucine-rich repeat kinase 2 FINDINGS: In comparison with healthy controls, we found that fibroblasts from patients with iPD or LRRK2-PD had a high amount of mitochondrial 7S DNA along with a low mtDNA replication rate that was associated with a reduction of cf-mtDNA release. Accumulation of 7S DNA in iPD and LRRK2-PD fibroblasts was related with an increase in H-strand mtDNA transcription. INTERPRETATION: These results show that 7S DNA accumulation, low mtDNA replication, high H-strand transcription, and low mtDNA release compose a pattern of mtDNA dysfunction shared by both iPD and LRRK2-PD fibroblasts. Moreover, these results suggest that the deregulation of the genetic switch formed by 7SDNA that alternates between mtDNA replication and transcription is a fundamental pathophysiological mechanism in both idiopathic and monogenic Parkinson's disease.

6 Article Whole-genome DNA hyper-methylation in iPSC-derived dopaminergic neurons from Parkinson's disease patients. 2019

Fernández-Santiago, Rubén / Merkel, Angelika / Castellano, Giancarlo / Heath, Simon / Raya, Ángel / Tolosa, Eduard / Martí, María-José / Consiglio, Antonella / Ezquerra, Mario. ·Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. ruben.fernandez.santiago@gmail.com. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. ruben.fernandez.santiago@gmail.com. · Statistical Genomics Team at the Centro Nacional de Análisis Genómico (CNAG-CRG), Centre de Regulacio Genómico (CRG), The Barcelona Institute of Science and Technology, 08028, Barcelona, Spain. · Dept. of Anatomic Pathology, Pharmacology and Microbiology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, 08908, Barcelona, Spain. · Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 28029, Madrid, Spain. · Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010, Barcelona, Spain. · Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. · Movement Disorders Unit, Dept. of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, 08036, Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Faculty of Medicine, Instituto de Investigación Biomédica de Bellvitge (IDIBELL), University of Barcelona, 08907, Barcelona, Spain. · Institute of Biomedicine of the University of Barcelona (IBUB), 08028, Barcelona, Spain. · Department of Molecular and Translational Medicine, University of Brescia, 25123, Brescia, Italy. · Department of Neurology, Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Faculty of Medicine (UB), University of Barcelona, Casanova 143, Floor 3B, 08036, Barcelona, Spain. ezquerra@clinic.ub.es. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), 28031, Madrid, Spain. ezquerra@clinic.ub.es. ·Clin Epigenetics · Pubmed #31337434.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) is characterized by the loss of midbrain dopaminergic neurons (DAn). Previously, we described the presence of DNA hyper- and hypo-methylation alterations in induced pluripotent stem cells (iPSC)-derived DAn from PD patients using the Illumina 450K array which prominently covers gene regulatory regions. METHODS: To expand and contextualize previous findings, we performed the first whole-genome DNA bisulfite sequencing (WGBS) using iPSC-derived DAn from representative PD subjects: one sporadic PD (sPD) patient, one monogenic LRRK2-associated PD patient (L2PD), and one control. RESULTS: At the whole-genome level, we detected global DNA hyper-methylation in the PD which was similarly spread across the genome in both sPD and L2PD and mostly affected intergenic regions. CONCLUSION: This study implements previous epigenetic knowledge in PD at a whole genome level providing the first comprehensive and unbiased CpG DNA methylation data using iPSC-derived DAn from PD patients. Our results indicate that DAn from monogenic or sporadic PD exhibit global DNA hyper-methylation changes. Findings from this exploratory study are to be validated in further studies analyzing other PD cell models and patient tissues.

7 Article SNCA and mTOR Pathway Single Nucleotide Polymorphisms Interact to Modulate the Age at Onset of Parkinson's Disease. 2019

Fernández-Santiago, Rubén / Martín-Flores, Núria / Antonelli, Francesca / Cerquera, Catalina / Moreno, Verónica / Bandres-Ciga, Sara / Manduchi, Elisabetta / Tolosa, Eduard / Singleton, Andrew B / Moore, Jason H / Anonymous3481045 / Martí, María-Josep / Ezquerra, Mario / Malagelada, Cristina. ·Lab of Parkinson Disease and Other Neurodegenerative Movement Disorders, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Catalonia, Spain. · Neurology Service, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain. · Networked Centre for Biomedical Research of Neurodegenerative Diseases, Madrid, Spain. · Department of Biomedicine, Unit of Biochemistry, Universitat de Barcelona, Barcelona, Catalonia, Spain. · Institute of Neurosciences, University of Barcelona, Barcelona, Catalonia, Spain. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. · Instituto de Investigación Biosanitaria de Granada (ibs. GRANADA), Granada, Spain. · The Perelman School of Medicine University of Pennsylvania, Philadelphia, Pennsylvania, USA. ·Mov Disord · Pubmed #31234232.

ABSTRACT: BACKGROUND: Single nucleotide polymorphisms (SNPs) in the α-synuclein (SNCA) gene are associated with differential risk and age at onset (AAO) of both idiopathic and Leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD). Yet potential combinatory or synergistic effects among several modulatory SNPs for PD risk or AAO remain largely underexplored. OBJECTIVES: The mechanistic target of rapamycin (mTOR) signaling pathway is functionally impaired in PD. Here we explored whether SNPs in the mTOR pathway, alone or by epistatic interaction with known susceptibility factors, can modulate PD risk and AAO. METHODS: Based on functional relevance, we selected a total of 64 SNPs mapping to a total of 57 genes from the mTOR pathway and genotyped a discovery series cohort encompassing 898 PD patients and 921 controls. As a replication series, we screened 4170 PD and 3014 controls available from the International Parkinson's Disease Genomics Consortium. RESULTS: In the discovery series cohort, we found a 4-loci interaction involving STK11 rs8111699, FCHSD1 rs456998, GSK3B rs1732170, and SNCA rs356219, which was associated with an increased risk of PD (odds ratio = 2.59, P < .001). In addition, we also found a 3-loci epistatic combination of RPTOR rs11868112 and RPS6KA2 rs6456121 with SNCA rs356219, which was associated (odds ratio = 2.89; P < .0001) with differential AAO. The latter was further validated (odds ratio = 1.56; P = 0.046-0.047) in the International Parkinson's Disease Genomics Consortium cohort. CONCLUSIONS: These findings indicate that genetic variability in the mTOR pathway contributes to SNCA effects in a nonlinear epistatic manner to modulate differential AAO in PD, unraveling the contribution of this cascade in the pathogenesis of the disease. © 2019 International Parkinson and Movement Disorder Society.

8 Article Mitochondrial and autophagic alterations in skin fibroblasts from Parkinson disease patients with Parkin mutations. 2019

González-Casacuberta, Ingrid / Juárez-Flores, Diana-Luz / Ezquerra, Mario / Fucho, Raquel / Catalán-García, Marc / Guitart-Mampel, Mariona / Tobías, Ester / García-Ruiz, Carmen / Fernández-Checa, José Carlos / Tolosa, Eduard / Martí, María-José / Grau, Josep Maria / Fernández-Santiago, Rubén / Cardellach, Francesc / Morén, Constanza / Garrabou, Glòria. ·Laboratory of Muscle Research and Mitochondrial Function, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Department of Internal Medicine, Hospital Clínic of Barcelona (HCB), Barcelona 08036, Spain. · Centro de Investigación Biomédica en Red (CIBER) de Enfermedades Raras (CIBERER), Madrid 28029, Spain. · Laboratory of Neurodegenerative Disorders, IDIBAPS, UB, Department of Neurology, HCB, Barcelona 08036, Spain. · CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid 28031, Spain. · Cell Death and Proliferation, IDIBAPS, Consejo Superior Investigaciones Científicas (CSIC), Barcelona, Spain. · Liver Unit, HCB, IDIBAPS and CIBER de Enfermedades Hepáticas y Digestivas (CIBEREHD), Barcelona, Spain. · USC Research Center for ALPD, Keck School of Medicine, Los Angeles, CA 90033, USA. ·Aging (Albany NY) · Pubmed #31180333.

ABSTRACT: PRKN encodes an E3-ubiquitin-ligase involved in multiple cell processes including mitochondrial homeostasis and autophagy. Previous studies reported alterations of mitochondrial function in fibroblasts from patients with PRKN mutation-associated Parkinson's disease (PRKN-PD) but have been only conducted in glycolytic conditions, potentially masking mitochondrial alterations. Additionally, autophagy flux studies in this cell model are missing.We analyzed mitochondrial function and autophagy in PRKN-PD skin-fibroblasts (n=7) and controls (n=13) in standard (glucose) and mitochondrial-challenging (galactose) conditions.In glucose, PRKN-PD fibroblasts showed preserved mitochondrial bioenergetics with trends to abnormally enhanced mitochondrial respiration that, accompanied by decreased CI, may account for the increased oxidative stress. In galactose, PRKN-PD fibroblasts exhibited decreased basal/maximal respiration vs. controls and reduced mitochondrial CIV and oxidative stress compared to glucose, suggesting an inefficient mitochondrial oxidative capacity to meet an extra metabolic requirement. PRKN-PD fibroblasts presented decreased autophagic flux with reduction of autophagy substrate and autophagosome synthesis in both conditions.The alterations exhibited under neuron-like oxidative environment (galactose), may be relevant to the disease pathogenesis potentially explaining the increased susceptibility of dopaminergic neurons to undergo degeneration. Abnormal PRKN-PD phenotype supports the usefulness of fibroblasts to model disease and the view of PD as a systemic disease where molecular alterations are present in peripheral tissues.

9 Article MTOR Pathway-Based Discovery of Genetic Susceptibility to L-DOPA-Induced Dyskinesia in Parkinson's Disease Patients. 2019

Martín-Flores, Núria / Fernández-Santiago, Rubén / Antonelli, Francesa / Cerquera, Catalina / Moreno, Verónica / Martí, Maria Josep / Ezquerra, Mario / Malagelada, Cristina. ·Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain. · Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain. · IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, 08036, Barcelona, Catalonia, Spain. · Neurology Service, Hospital Clínic de Barcelona, Barcelona, Catalonia, Spain. · Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Neurology Unit, Medical School, Hospital Universitario San Ignacio, Pontificia Universidad Javeriana, Bogotá, Colombia. · Department of Biomedicine, Unit of Biochemistry, Faculty of Medicine, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain. cristina.malagelada@ub.edu. · Institut de Neurociències, Universitat de Barcelona, 08036, Barcelona, Catalonia, Spain. cristina.malagelada@ub.edu. ·Mol Neurobiol · Pubmed #29992529.

ABSTRACT: Dyskinesia induced by L-DOPA administration (LID) is one of the most invalidating adverse effects of the gold standard treatment restoring dopamine transmission in Parkinson's disease (PD). However, LID manifestation in parkinsonian patients is variable and heterogeneous. Here, we performed a candidate genetic pathway analysis of the mTOR signaling cascade to elucidate a potential genetic contribution to LID susceptibility, since mTOR inhibition ameliorates LID in PD animal models. We screened 64 single nucleotide polymorphisms (SNPs) mapping to 57 genes of the mTOR pathway in a retrospective cohort of 401 PD cases treated with L-DOPA (70 PD with moderate/severe LID and 331 with no/mild LID). We performed classic allelic, genotypic, and epistatic analyses to evaluate the association of individual or combinations of SNPs with LID onset and with LID severity after initiation of L-DOPA treatment. As for the time to LID onset, we found significant associations with SNP rs1043098 in the EIF4EBP2 gene and also with an epistatic interaction involving EIF4EBP2 rs1043098, RICTOR rs2043112, and PRKCA rs4790904. For LID severity, we found significant association with HRAS rs12628 and PRKN rs1801582 and also with a four-loci epistatic combination involving RPS6KB1 rs1292034, HRAS rs12628, RPS6KA2 rs6456121, and FCHSD1 rs456998. These findings indicate that the mTOR pathway contributes genetically to LID susceptibility. Our study could help to identify the most susceptible PD patients to L-DOPA in order to prevent the appearance of early and/or severe LID in a future. This information could also be used to stratify PD patients in clinical trials in a more accurate way.

10 Article MicroRNA alterations in iPSC-derived dopaminergic neurons from Parkinson disease patients. 2018

Tolosa, Eduard / Botta-Orfila, Teresa / Morató, Xavier / Calatayud, Carles / Ferrer-Lorente, Raquel / Martí, María-José / Fernández, Manel / Gaig, Carles / Raya, Ángel / Consiglio, Antonella / Ezquerra, Mario / Fernández-Santiago, Rubén. ·Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Gene Function and Evolution Group, Centre for Genomic Regulation (CRG), Barcelona, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain. · Departament Patologia i Terapèutica Experimental, Unitat de Farmacologia, Facultat de Medicina, IDIBELL-Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain; Institut de Neurociències, Universitat de Barcelona, Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Institute of Biomedicine of the University of Barcelona (IBUB), Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain. · Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain; Department of Neurology, Multidisciplinary Sleep Unit, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Institute of Biomedicine of the University of Barcelona (IBUB), Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona, Spain; Department of Pathology and Experimental Therapeutics, Faculty of Medicine, IDIBELL- University of Barcelona, Barcelona, Spain; Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Brescia, Italy. Electronic address: consiglio@ub.es. · Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: ezquerra@clinic.ub.es. · Department of Neurology, Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. Electronic address: ruben.fernandez.santiago@gmail.com. ·Neurobiol Aging · Pubmed #29935433.

ABSTRACT: MicroRNA (miRNA) misregulation in peripheral blood has been linked to Parkinson disease (PD) but its role in the disease progression remains elusive. We performed an explorative genome-wide study of miRNA expression levels in dopaminergic neurons (DAn) from PD patients generated by somatic cell reprogramming and induced pluripotent stem cells differentiation. We quantified expression levels of 377 miRNAs in DAn from 3 sporadic PD patients (sPD), 3 leucine-rich repeat kinase 2-associated PD patients (L2PD) (total 6 PD), and 4 healthy controls. We identified differential expression of 10 miRNA of which 5 were upregulated in PD (miR-9-5p, miR-135a-5p, miR-135b-5p, miR-449a, and miR-449b-5p) and 5 downregulated (miR-141-3p, miR-199a-5p, miR-299-5p, miR-518e-3p, and miR-519a-3p). Changes were similar in sPD and L2PD. Integrative analysis revealed significant correlations between miRNA/mRNA expression. Moreover, upregulation of miR-9-5p and miR-135b-5p was associated with downregulation of transcription factors related to the DNA hypermethylation of enhancer elements in PD DAn (FOXA1 and NR3C1). In summary, miRNA changes are associated with monogenic L2PD and sPD and co-occur with epigenetic changes in DAn from PD patients.

11 Article Exhaustion of mitochondrial and autophagic reserve may contribute to the development of LRRK2 2018

Juárez-Flores, Diana Luz / González-Casacuberta, Ingrid / Ezquerra, Mario / Bañó, María / Carmona-Pontaque, Francesc / Catalán-García, Marc / Guitart-Mampel, Mariona / Rivero, Juan José / Tobias, Ester / Milisenda, Jose Cesar / Tolosa, Eduard / Marti, Maria Jose / Fernández-Santiago, Ruben / Cardellach, Francesc / Morén, Constanza / Garrabou, Glòria. ·Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. · Laboratory of Parkinson disease and other Neurodegenerative Movement Disorders: Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain. · CIBER de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain. · Department of Genetics, Microbiology and Statistics, University of Barcelona, Barcelona, Spain. · Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. cmoren1@clinic.ub.es. · Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. cmoren1@clinic.ub.es. · Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Department of Internal Medicine-Hospital Clínic of Barcelona, Faculty of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Spain. garrabou@clinic.ub.es. · Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. garrabou@clinic.ub.es. ·J Transl Med · Pubmed #29884186.

ABSTRACT: BACKGROUND: Mutations in leucine rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD). Mitochondrial and autophagic dysfunction has been described as etiologic factors in different experimental models of PD. We aimed to study the role of mitochondria and autophagy in LRRK2 METHODS: Fibroblasts from six non-manifesting LRRK2 RESULTS: A similar mitochondrial phenotype of NM-LRRK2 CONCLUSIONS: Enhanced mitochondrial performance of NM-LRRK2

12 Article Transcriptional alterations in skin fibroblasts from Parkinson's disease patients with parkin mutations. 2018

González-Casacuberta, Ingrid / Morén, Constanza / Juárez-Flores, Diana-Luz / Esteve-Codina, Anna / Sierra, Cristina / Catalán-García, Marc / Guitart-Mampel, Mariona / Tobías, Ester / Milisenda, José César / Pont-Sunyer, Claustre / Martí, María José / Cardellach, Francesc / Tolosa, Eduard / Artuch, Rafael / Ezquerra, Mario / Fernández-Santiago, Rubén / Garrabou, Glòria. ·Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Sciences, University of Barcelona (UB), Department of Internal Medicine-Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain; Universitat Pompeu Fabra (UPF), Barcelona, Spain. · Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain. · Laboratory of Parkison Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research-CELLEX, IDIBAPS, Faculty of Medicine and Health Sciences, UB, Department of Neurology-Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain; Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, Barcelona, Spain. · Laboratory of Parkison Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research-CELLEX, IDIBAPS, Faculty of Medicine and Health Sciences, UB, Department of Neurology-Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: EZQUERRA@clinic.cat. · Laboratory of Parkison Disease and Other Neurodegenerative Movement Disorders: Clinical and Experimental Research-CELLEX, IDIBAPS, Faculty of Medicine and Health Sciences, UB, Department of Neurology-Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: ruben.fernandez.santiago@gmail.com. · Laboratory of Muscle Research and Mitochondrial Function-CELLEX, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Faculty of Medicine and Health Sciences, University of Barcelona (UB), Department of Internal Medicine-Hospital Clínic of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain. Electronic address: GARRABOU@clinic.cat. ·Neurobiol Aging · Pubmed #29501959.

ABSTRACT: Mutations in the parkin gene (PRKN) are the most common cause of autosomal-recessive juvenile Parkinson's disease (PD). PRKN encodes an E3 ubiquitin ligase that is involved in multiple regulatory functions including proteasomal-mediated protein turnover, mitochondrial function, mitophagy, and cell survival. However, the precise molecular events mediated by PRKN mutations in PRKN-associated PD (PRKN-PD) remain unknown. To elucidate the cellular impact of parkin mutations, we performed an RNA sequencing study in skin fibroblasts from PRKN-PD patients carrying different PRKN mutations (n = 4) and genetically unrelated healthy subjects (n = 4). We identified 343 differentially expressed genes in PRKN-PD fibroblasts. Gene ontology and canonical pathway analysis revealed enrichment of differentially expressed genes in processes such as cell adhesion, cell growth, and amino acid and folate metabolism among others. Our findings indicate that PRKN mutations are associated with large global gene expression changes as observed in fibroblasts from PRKN-PD patients and support the view of PD as a systemic disease affecting also non-neural peripheral tissues such as the skin.

13 Article α-synuclein (SNCA) but not dynamin 3 (DNM3) influences age at onset of leucine-rich repeat kinase 2 (LRRK2) Parkinson's disease in Spain. 2018

Fernández-Santiago, Rubén / Garrido, Alicia / Infante, Jon / González-Aramburu, Isabel / Sierra, María / Fernández, Manel / Valldeoriola, Francesc / Muñoz, Esteban / Compta, Yaroslau / Martí, María-José / Ríos, José / Tolosa, Eduardo / Ezquerra, Mario / Anonymous6830937. ·Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Clinical and Experimental Research, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas, Madrid, Spain. · Movement Disorders Unit, Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. · Movement Disorders Unit, Department of Neurology, Hospital Universitario Marqués de Valdecilla, Universidad de Cantabria, Santander, Spain. · Medical Statistics Core Facility, Institut d'Investigacions Biomèdiques August Pi i Sunyer and Hospital Clinic, Barcelona, Spain. · Biostatistics Unit, Faculty of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. ·Mov Disord · Pubmed #29473656.

ABSTRACT: OBJECTIVES: A recent study showed that Arab-Berbers GG homozygous at rs2421947(C/G) in the dynamin 3 gene (DNM3) had 12.5 years earlier age at onset of leucine-rich repeat kinase 2 (LRRK2)-associated Parkinson's disease (PD) (L2PD). We explored whether this variant modulates the L2PD age at onset in Spain. METHODS: We genotyped rs2421947 in 329 participants (210 L2PD patients, 119 L2PD nonmanifesting p.G2019S carriers), and marker rs356219 (A/G) in the α-synuclein gene (SNCA). RESULTS: By Kaplan Meier and Cox regression analyses, we did not find an association of the DNM3 polymorphism with L2PD age at onset. However, we found an association of the SNCA marker with up to an 11 years difference in the L2PD median age at onset (58 years for GG carriers vs 69 years for AA). CONCLUSION: Our results indicate that SNCA rs356219 but not dynamin 3 DNM3 rs2421947 modifies the penetrance of the mutation G2019S in the Spanish population by influencing the L2PD age at onset. These findings suggest that different genetic modifiers may influence the L2PD age at onset in different populations. © 2018 International Parkinson and Movement Disorder Society.

14 Article The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against α-Synuclein-Induced Toxicity. 2018

Kim, Hanna / Calatayud, Carles / Guha, Sanjib / Fernández-Carasa, Irene / Berkowitz, Laura / Carballo-Carbajal, Iria / Ezquerra, Mario / Fernández-Santiago, Rubén / Kapahi, Pankaj / Raya, Ángel / Miranda-Vizuete, Antonio / Lizcano, Jose Miguel / Vila, Miquel / Caldwell, Kim A / Caldwell, Guy A / Consiglio, Antonella / Dalfo, Esther. ·Department of Biological Sciences, The University of Alabama, Tuscaloosa, AL, 35487, USA. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain. · Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital Duran i Reynals, 08908, L'Hospitalet de Llobregat, Spain. · Buck Institute for Research on Aging, 8001 Redwood Boulevard, Novato, CA, 94945, USA. · Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute-Center for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), 08035, Barcelona, Spain. · Laboratory of Parkinson Disease and Other Neurodegenerative Movement Disorders, Department of Neurology: Clinical and Experimental Research, IDIBAPS - Hospital Clínic de Barcelona, 08036, Barcelona, Spain. · Catalan Institution for Research and Advanced Studies (ICREA), 08010, Barcelona, Spain. · Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/ Universidad de Sevilla, 41013, Sevilla, Spain. · Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, 08028, L'Hospitalet de Llobregat, Spain. consiglio@ub.edu. · Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08908, Spain. consiglio@ub.edu. · Department of Molecular and Translational Medicine, University of Brescia, Brescia, Spain. consiglio@ub.edu. · Department of Biochemistry and Molecular Biology, Institut de Neurociències, Faculty of Medicine, M2, Universitat Autònoma de Barcelona (UAB), Bellaterra Campus, Cerdanyola del Vallés, Barcelona, Spain. esther.dalfo@uab.cat. · Faculty of Medicine, University of Vic-Central University of Catalonia (UVic-UCC), Can Baumann, 08500, Vic, Spain. esther.dalfo@uab.cat. ·Mol Neurobiol · Pubmed #29429047.

ABSTRACT: Parkinson's disease is associated with intracellular α-synuclein accumulation and ventral midbrain dopaminergic neuronal death in the Substantia Nigra of brain patients. The Rho GTPase pathway, mainly linking surface receptors to the organization of the actin and microtubule cytoskeletons, has been suggested to participate to Parkinson's disease pathogenesis. Nevertheless, its exact contribution remains obscure. To unveil the participation of the Rho GTPase family to the molecular pathogenesis of Parkinson's disease, we first used C elegans to demonstrate the role of the small GTPase RAC1 (ced-10 in the worm) in maintaining dopaminergic function and survival in the presence of alpha-synuclein. In addition, ced-10 mutant worms determined an increase of alpha-synuclein inclusions in comparison to control worms as well as an increase in autophagic vesicles. We then used a human neuroblastoma cells (M17) stably over-expressing alpha-synuclein and found that RAC1 function decreased the amount of amyloidogenic alpha-synuclein. Further, by using dopaminergic neurons derived from patients of familial LRRK2-Parkinson's disease we report that human RAC1 activity is essential in the regulation of dopaminergic cell death, alpha-synuclein accumulation, participates in neurite arborization and modulates autophagy. Thus, we determined for the first time that RAC1/ced-10 participates in Parkinson's disease associated pathogenesis and established RAC1/ced-10 as a new candidate for further investigation of Parkinson's disease associated mechanisms, mainly focused on dopaminergic function and survival against α-synuclein-induced toxicity.

15 Article Discovering the 3' UTR-mediated regulation of alpha-synuclein. 2017

Marchese, Domenica / Botta-Orfila, Teresa / Cirillo, Davide / Rodriguez, Juan Antonio / Livi, Carmen Maria / Fernández-Santiago, Rubén / Ezquerra, Mario / Martí, Maria J / Bechara, Elias / Tartaglia, Gian Gaetano / Anonymous2250927. ·Centre for Genomic Regulation (CRG), The Barcelona Institute for Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain. · Universitat Pompeu Fabra (UPF), Barcelona, Spain. · Barcelona Supercomputing Center (BSC), Torre Girona c/Jordi Girona, 29, 08034 Barcelona, Spain. · Centro Nacional de Análisis Genómico, c/BaldiriReixac, 4, 08028 Barcelona, Spain. · IFOM, the FIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milan, Italy. · Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. · Parkinson's Disease and Movement Disorders Unit, Institut de Neurociències Hospital Clínic, CIBERNED, Barcelona, Spain. · Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. ·Nucleic Acids Res · Pubmed #29149290.

ABSTRACT: Recent evidence indicates a link between Parkinson's Disease (PD) and the expression of a-synuclein (SNCA) isoforms with different 3' untranslated regions (3'UTRs). Yet, the post-transcriptional mechanisms regulating SNCA expression are unknown. Using a large-scale in vitro /in silico screening we identified RNA-binding proteins (RBPs) that interact with SNCA 3' UTRs. We identified two RBPs, ELAVL1 and TIAR, that bind with high affinity to the most abundant and translationally active 3' UTR isoform (575 nt). Knockdown and overexpression experiments indicate that both ELAVL1 and TIAR positively regulate endogenous SNCA in vivo. The mechanism of regulation implies mRNA stabilization as well as enhancement of translation in the case of TIAR. We observed significant alteration of both TIAR and ELAVL1 expression in motor cortex of post-mortem brain donors and primary cultured fibroblast from patients affected by PD and Multiple System Atrophy (MSA). Moreover, trans expression quantitative trait loci (trans-eQTLs) analysis revealed that a group of single nucleotide polymorphisms (SNPs) in TIAR genomic locus influences SNCA expression in two different brain areas, nucleus accumbens and hippocampus. Our study sheds light on the 3' UTR-mediated regulation of SNCA and its link with PD pathogenesis, thus opening up new avenues for investigation of post-transcriptional mechanisms in neurodegeneration.

16 Article A Novel p.Glu298Lys Mutation in the ACMSD Gene in Sporadic Parkinson's Disease. 2017

Vilas, Dolores / Fernández-Santiago, Rubén / Sanchez, Elena / Azcona, Luis J / Santos-Montes, Meritxell / Casquero, Pilar / Argandoña, Lucía / Tolosa, Eduardo / Paisán-Ruiz, Coro. ·Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Barcelona, Spain. · Department of Neurology, Laboratory of Neurodegenerative Disorders, Hospital Clínic de Barcelona, Barcelona, Spain. · Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain. · Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Spain. · Department of Neurology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. · Department of Neurosciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. · Neurology Service, Hospital Mateu Orfila, Maó, Menorca, Spain. · Departments of Psychiatry and Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. · Friedman Brain and Mindich Child Health and Development Institutes, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, USA. ·J Parkinsons Dis · Pubmed #28671144.

ABSTRACT: BACKGROUND: Common genetic variability in the ACMSD gene has been associated with increased risk for Parkinson's disease (PD) but ACMSD mutations in clinical cases of PD have so far not been reported. OBJECTIVE: To describe a case of sporadic PD carrying a novel ACMSD mutation. METHODS: As part of a genetic study to identify potential pathogenic gene defects related to PD in the Mediterranean island Menorca, an initial group of 62 PD patients underwent mutational screening using a panel-based sequencing approach. RESULTS: We report a 74-years-old man with sporadic PD who developed tremor in his right hand and slowness. On examination, moderate rigidity, asymmetric bradykinesia, and bilateral action tremor were present. He was started on levodopa with significant improvement. Two years later, he developed wearing off phenomena. The genetic study in the patient identified a novel ACMSD mutation resulting in p.Glu298Lys amino-acid change which was not present in neurologically normal population. CONCLUSIONS: Our data suggest that not only common genetic variability but also rare variants in ACMSD alone or in combination with other risk factors might increase the risk of PD.

17 Article The prodromal phase of leucine-rich repeat kinase 2-associated Parkinson disease: Clinical and imaging Studies. 2017

Pont-Sunyer, Claustre / Tolosa, Eduardo / Caspell-Garcia, Chelsea / Coffey, Christopher / Alcalay, Roy N / Chan, Piu / Duda, John E / Facheris, Maurizio / Fernández-Santiago, Rubén / Marek, Kenneth / Lomeña, Francisco / Marras, Connie / Mondragon, Elisabet / Saunders-Pullman, Rachel / Waro, Bjorg / Anonymous300902. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Neurology Unit, Hospital General de Granollers, Universitat Internacional de Catalunya, Granollers, Spain. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, New York, USA. · Departments of Neurology and Neurobiology, Xuanwu Hospital of Capital Medical University, Beijing, China. · Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona, Institutd'InvestigacionsBiomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, and the Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. · Institute for Neurodegenerative Disorders and Molecular NeuroImaging, New Haven, Connecticut, USA. · Department of Nuclear Medicine, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain. · Toronto Western Hospital Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Ontario, Canada. · Department of Neurology, Movement Disorders Unit. Hospital Universitario Donostia. Biodonostia Research Institute, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), San Sebastián, Guipúzcoa, Spain. · Department of Neurology, Mount Sinai Beth Israel Medical Center and Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Department of Neurology, Norwegian University of Science and Technology, Trondheim, Norway. ·Mov Disord · Pubmed #28370517.

ABSTRACT: BACKGROUND: Asymptomatic, nonmanifesting carriers of leucine-rich repeat kinase 2 mutations are at increased risk of developing PD. Clinical and neuroimaging features may be associated with gene carriage and/or may demarcate individuals at greater risk for phenoconversion to PD. OBJECTIVES: To investigate clinical and dopamine transporter single-photon emission computed tomography imaging characteristics of leucine-rich repeat kinase 2 asymptomatic carriers. METHODS: A total of 342 carriers' and 259 noncarriers' relatives of G2019S leucine-rich repeat kinase 2/PD patients and 39 carriers' and 31 noncarriers' relatives of R1441G leucine-rich repeat kinase 2/PD patients were evaluated. Motor and nonmotor symptoms were assessed using specific scales and questionnaires. Neuroimaging quantitative data were obtained in 81 carriers and compared with 41 noncarriers. RESULTS: G2019S carriers scored higher in motor scores and had lower radioligand uptake compared to noncarriers, but no differences in nonmotor symptoms scores were observed. R1441G carriers scored higher in motor scores, had lower radioligand uptake, and had higher scores in depression, dysautonomia, and Rapid Eye Movements Sleep Behavior Disorder Screening Questionnaire scores, but had better cognition scores than noncarriers. Among G2019S carriers, a group with "mild motor signs" was identified, and was significantly older, with worse olfaction and lower radioligand uptake. CONCLUSIONS: G2019S and R1441G carriers differ from their noncarriers' relatives in higher motor scores and slightly lower radioligand uptake. Nonmotor symptoms were mild, and different nonmotor profiles were observed in G2019S carriers compared to R1441G carriers. A group of G2019S carriers with known prodromal features was identified. Longitudinal studies are required to determine whether such individuals are at short-term risk of developing overt parkinsonism. © 2017 International Parkinson and Movement Disorder Society.

18 Article Motor and nonmotor heterogeneity of LRRK2-related and idiopathic Parkinson's disease. 2016

Marras, Connie / Alcalay, Roy N / Caspell-Garcia, Chelsea / Coffey, Christopher / Chan, Piu / Duda, John E / Facheris, Maurizio F / Fernández-Santiago, Rubén / Ruíz-Martínez, Javier / Mestre, Tiago / Saunders-Pullman, Rachel / Pont-Sunyer, Claustre / Tolosa, Eduardo / Waro, Bjorg / Anonymous1390865. ·Toronto Western Hospital Morton and Gloria Shulman Movement Disorders Centre and the Edmond J. Safra Program in Parkinson's Disease, University of Toronto, Toronto, Ontario, Canada. · Department of Neurology, Columbia University Medical Center, New York, New York, USA. · Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, Iowa, USA. · Departments of Neurology and Neurobiology, Xuanwu Hospital of Capital Medical University, China. · Parkinson's Disease Research, Education and Clinical Center, Michael J. Crescenz VA Medical Center and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA. · Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, and the Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid, Spain. · Department of Neurology (Movement Disorders Unit), Hospital Universitario Donostia. Biodonostia Research Institute, Neurosciences area. San Sebastián, Guipúzcoa, Spain, and CIBERNED, Carlos III Health Institute, Madrid, Spain. · Parkinson's Disease and Movement Disorder Centre, Division of Neurology, Department of Medicine, The Ottawa Hospital, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. · Department of Neurology, Mount Sinai Beth Israel Medical Center and Icahn School of Medicine at Mount Sinai, New York, New York, USA. · Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institutd'InvestigacionsBiomediquesAugust Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Department of Neurology, Norwegian University of Science and Technology, Trondheim, Norway. ·Mov Disord · Pubmed #27091104.

ABSTRACT: BACKGROUND: Parkinson's disease (PD) associated with LRRK2 mutations has been described as similar to idiopathic PD with minor clinical differences. No study has compared the clinical features of LRRK2-associated PD due to different mutations. The objective of this study was to compare LRRK2-associated PD due to G2019S and G2385R mutations and to compare each to idiopathic PD. METHODS: Sites within the international LRRK2 Cohort Consortium undertook family-based, community-based, or clinic-based studies to gather clinical data on manifesting carriers and patients with idiopathic PD. RESULTS: Five hundred sixteen PD patients with the G2019S mutation, 199 with the G2385R mutation, and 790 patients with idiopathic PD were included in the data set. Adjusted for age, sex, disease duration, and levodopa-equivalent daily dose, mean MDS-UPDRS part II or III scores and the frequency of motor fluctuations were higher in the G2385R mutation carriers than in either the G2019S mutation carriers or idiopathic PD patients. G2019S mutation carriers had significantly lower UPDRS part III scores than idiopathic PD patients. Both G2019S and G2385R mutation carriers had a higher proportion of the postural instability gait disorder phenotype compared with idiopathic PD patients. LRRK2 G2019S PD patients had better UPSIT scores and lower Geriatric Depression Scale scores than idiopathic PD patients in adjusted analyses. CONCLUSIONS: G2385R and G2019S PD appear to have motor differences that may be explained by contrasting local treatment or measurement practices or differences in the biology of the disease. Longitudinal studies should evaluate whether progression is faster in G2385R mutation carriers compared with G2019S PD or idiopathic PD. © 2016 International Parkinson and Movement Disorder Society.

19 Article Aberrant epigenome in iPSC-derived dopaminergic neurons from Parkinson's disease patients. 2015

Fernández-Santiago, Rubén / Carballo-Carbajal, Iria / Castellano, Giancarlo / Torrent, Roger / Richaud, Yvonne / Sánchez-Danés, Adriana / Vilarrasa-Blasi, Roser / Sánchez-Pla, Alex / Mosquera, José Luis / Soriano, Jordi / López-Barneo, José / Canals, Josep M / Alberch, Jordi / Raya, Ángel / Vila, Miquel / Consiglio, Antonella / Martín-Subero, José I / Ezquerra, Mario / Tolosa, Eduardo. ·Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain ruben.fernandez.santiago@gmail.com ezquerra@clinic.ub.es. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Neurodegenerative Diseases Research Laboratory, Hospital Vall d'Hebron Vall d'Hebron Research Institute (VHIR) Universitat Autònoma de Barcelona (UAB), Barcelona, Spain. · Department of Pathological Anatomy, Pharmacology and Microbiology, University of Barcelona (UB) Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. · Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain. · Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Centre for Networked Biomedical Research on Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain. · Department of Statistics, University of Barcelona (UB), Barcelona, Spain Department of Statistics, Vall d'Hebron Research Institute (VHIR), Barcelona, Spain. · Department of Statistics, University of Barcelona (UB), Barcelona, Spain. · Departament d'Estructura i Constituents de la Matèria (ECM), Facultat de Física, University of Barcelona (UB), Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Institute of Biomedicine of Seville (IBiS) Hospital Universitario Virgen del Rocío Consejo Superior de Investigaciones Científicas (CSIC) University of Seville, Seville, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain Department of Cell Biology, Immunology and Neuroscience, Faculty of Medicine, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain. · Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain Centre for Networked Biomedical Research on Bioengineering Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. · Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Neurodegenerative Diseases Research Laboratory, Hospital Vall d'Hebron Vall d'Hebron Research Institute (VHIR) Universitat Autònoma de Barcelona (UAB), Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. · Institute for Biomedicine (IBUB) University of Barcelona (UB), Barcelona, Spain Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, Brescia, Italy. · Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain Cell Therapy Program, Faculty of Medicine, University of Barcelona (UB), Barcelona, Spain Movement Disorders Unit, Department of Neurology, Hospital Clínic of Barcelona Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) University of Barcelona (UB), Barcelona, Spain. ·EMBO Mol Med · Pubmed #26516212.

ABSTRACT: The epigenomic landscape of Parkinson's disease (PD) remains unknown. We performed a genomewide DNA methylation and a transcriptome studies in induced pluripotent stem cell (iPSC)-derived dopaminergic neurons (DAn) generated by cell reprogramming of somatic skin cells from patients with monogenic LRRK2-associated PD (L2PD) or sporadic PD (sPD), and healthy subjects. We observed extensive DNA methylation changes in PD DAn, and of RNA expression, which were common in L2PD and sPD. No significant methylation differences were present in parental skin cells, undifferentiated iPSCs nor iPSC-derived neural cultures not-enriched-in-DAn. These findings suggest the presence of molecular defects in PD somatic cells which manifest only upon differentiation into the DAn cells targeted in PD. The methylation profile from PD DAn, but not from controls, resembled that of neural cultures not-enriched-in-DAn indicating a failure to fully acquire the epigenetic identity own to healthy DAn in PD. The PD-associated hypermethylation was prominent in gene regulatory regions such as enhancers and was related to the RNA and/or protein downregulation of a network of transcription factors relevant to PD (FOXA1, NR3C1, HNF4A, and FOSL2). Using a patient-specific iPSC-based DAn model, our study provides the first evidence that epigenetic deregulation is associated with monogenic and sporadic PD.

20 Article Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers. 2015

Pont-Sunyer, Claustre / Iranzo, Alex / Gaig, Carles / Fernández-Arcos, Ana / Vilas, Dolores / Valldeoriola, Francesc / Compta, Yaroslau / Fernández-Santiago, Ruben / Fernández, Manel / Bayés, Angels / Calopa, Matilde / Casquero, Pilar / de Fàbregues, Oriol / Jaumà, Serge / Puente, Victor / Salamero, Manel / José Martí, Maria / Santamaría, Joan / Tolosa, Eduard. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions BiomediquesAugust Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · MultidisciplinarySleepDisordersUnit, Neurology Service, Hospital Clinic de Barcelona, Universitat de Barcelona, Institut d'Investigacions BiomediquesAugust Pi I Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Laboratory of Neurodegenerative Disorders, Department of Clinical and Experimental Neurology, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Universitat de Barcelona, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain. · Unidad de Parkinson Teknon, Barcelona, Spain. · NeurologyService, Hospital Universitari de Bellvitge, Barcelona, Spain. · Hospital Mateu Orfila, Maó, Menorca, Spain. · Neurology Service, Hospital Universitari Vall D'Hebron, Barcelona, Spain. · Neurology Service, Hospital Del Mar, Barcelona, Spain. · PsychologyService, Hospital Clinic,Barcelona, Spain. ·PLoS One · Pubmed #26177462.

ABSTRACT: OBJECTIVE: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). METHODS: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. RESULTS: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. CONCLUSIONS: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD.

21 Article The MC1R melanoma risk variant p.R160W is associated with Parkinson disease. 2015

Tell-Marti, Gemma / Puig-Butille, Joan Anton / Potrony, Miriam / Badenas, Celia / Milà, Montserrat / Malvehy, Josep / Martí, María José / Ezquerra, Mario / Fernández-Santiago, Rubén / Puig, Susana. ·Dermatology, Department, Melanoma Unit, Hospital Clínic and August Pi i Sunyer Biomedical Research Institute (IDIBAPS); Center for Biomedical Network Research on Rare Diseases (CIBERER), Carlos III Health Institute (ISCIII). ·Ann Neurol · Pubmed #25631192.

ABSTRACT: Epidemiological studies have reported the co-occurrence of Parkinson disease (PD) and melanoma. Common genetic variants in the MC1R (melanocortin 1 receptor) gene, which determines skin and hair color, are associated with melanoma. Here we investigated whether genetic variants in MC1R modulate the risk of PD by sequencing the entire gene in 870 PD patients and 736 controls ascertained from Spain. We found that the MC1R variant p.R160W (rs1805008) is marginally associated with PD (odds ratio = 2.10, gender- and age-adjusted p = 0.009, Bonferroni-corrected p = 0.063). Our results suggest that MC1R genetic variants modulate the risk of PD disease in the Spanish population.

22 Article Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease. 2014

Romaní-Aumedes, J / Canal, M / Martín-Flores, N / Sun, X / Pérez-Fernández, V / Wewering, S / Fernández-Santiago, R / Ezquerra, M / Pont-Sunyer, C / Lafuente, A / Alberch, J / Luebbert, H / Tolosa, E / Levy, O A / Greene, L A / Malagelada, C. ·Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain. · Department of Pathology and Cell Biology, Columbia University, New York, NY, USA. · Department of Animal Physiology, Faculty for Biology, Ruhr University, Bochum, Germany. · 1] Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain. · Laboratory of Neurodegenerative Disorders and Department of Neurology, Institut Clínic de Neurociències, Hospital Clínic de Barcelona, Department of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain. · 1] Department of Pathological Anatomy, Pharmacology and Microbiology, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain [2] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain. · 1] IDIBAPS-Institut d'Investigacions Biomèdiques August Pi i Sunyer, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain [2] Department of Cell Biology, Immunology and Neurosciences, Faculty of Medicine, Universitat de Barcelona, Barcelona, Catalonia, Spain. · Department of Neurology Columbia University, New York, NY, USA. ·Cell Death Dis · Pubmed #25101677.

ABSTRACT: Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.

23 Article Identification of blood serum micro-RNAs associated with idiopathic and LRRK2 Parkinson's disease. 2014

Botta-Orfila, Teresa / Morató, Xavier / Compta, Yaroslau / Lozano, Juan José / Falgàs, Neus / Valldeoriola, Francesc / Pont-Sunyer, Claustre / Vilas, Dolores / Mengual, Lourdes / Fernández, Manel / Molinuevo, José Luis / Antonell, Anna / Martí, Maria José / Fernández-Santiago, Rubén / Ezquerra, Mario. ·Laboratory of Neurodegenerative Disorders, Department of Neurology, Hospital Clínic-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Centro de Investigación sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Catalonia, Spain. ·J Neurosci Res · Pubmed #24648008.

ABSTRACT: Blood-cell-free circulating micro-RNAs (miRNAs) have been proposed as potential accessible biomarkers for neurodegenerative diseases such as Parkinson's disease (PD). Here we analyzed the serum levels of 377 miRNAs in a discovery set of 10 idiopathic Parkinson's disease (IPD) patients, 10 PD patients carriers of the LRRK2 G2019S mutation (LRRK2 PD), and 10 controls by using real-time quantitative PCR-based TaqMan MicroRNA arrays. We detected candidate differentially expressed miRNAs, which were further tested in a first validation set consisting of 20 IPD, 20 LRRK2 PD, and 20 control samples. We found four statistically significant miRNAs that were downregulated in either LRRK2 or IPD (miR-29a, miR-29c, miR-19a, and miR-19b). Subsequently, we validated these findings in a third set of samples consisting of 65 IPD and 65 controls and confirmed the association of downregulated levels of miR-29c, miR-29a, and miR-19b in IPD. Differentially expressed miRNAs are predicted to target genes belonging to pathways related to ECM-receptor interaction, focal adhesion, MAPK, Wnt, mTOR, adipocytokine, and neuron projection. Results from our exploratory study indicate that downregulated levels of specific circulating serum miRNAs are associated with PD and suggest their potential use as noninvasive biomarkers for PD. Future studies should further confirm the association of these miRNAs with PD.

24 Article Age at onset in LRRK2-associated PD is modified by SNCA variants. 2012

Botta-Orfila, Teresa / Ezquerra, Mario / Pastor, Pau / Fernández-Santiago, Rubén / Pont-Sunyer, Claustre / Compta, Yaroslau / Lorenzo-Betancor, Oswaldo / Samaranch, Lluis / Martí, Maria José / Valldeoriola, Francesc / Calopa, Matilde / Fernández, Manel / Aguilar, Miquel / de Fabregas, Oriol / Hernández-Vara, Jorge / Tolosa, Eduard. ·Parkinson's Disease and Movement Disorders Unit, Neurology Service-Hospital Clínic, Institut de Neurociències and Department of Medicine, Universitat de Barcelona-Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. ·J Mol Neurosci · Pubmed #22669510.

ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) and α-synuclein (SNCA) genes are known genetic causes of Parkinson's disease (PD). Recently, a genetic variant in SNCA has been associated with a lower age at onset in idiopathic PD (IPD). We genotyped the SNCA polymorphism rs356219 in 84 LRRK2-associated PD patients carrying the G2019S mutation. We found that a SNCA genetic variant is associated with an earlier age at onset in LRRK2-associated PD. Our results support the notion that SNCA variants can modify the pathogenic effect of LRRK2 mutations as described previously for IPD.

25 Minor Reply. 2016

Tell-Martí, Gemma / Puig-Butille, Joan Anton / Potrony, Miriam / Badenas, Celia / Milà, Montserrat / Malvehy, Josep / Martí, María José / Ezquerra, Mario / Fernández-Santiago, Rubén / Puig, Susana. ·Dermatology Department, Melanoma Unit, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute. · Center for Networked Biomedical Research on Rare Diseases, Carlos III Health Institute. · Biochemical and Molecular Genetics Service, Hospital Clinic and August Pi i Sunyer Biomedical Research Institute. · Laboratory of Neurodegenerative Disorders, Department of Clinical and Experimental Neurology, August Pi i Sunyer Biomedical Research Institute, Hospital Clinic of Barcelona, Center for Networked Biomedical Research in Neurodegenerative Diseases. · Medicine Department, University of Barcelona, Barcelona, Spain. ·Ann Neurol · Pubmed #26389780.

ABSTRACT: -- No abstract --

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