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Parkinson Disease: HELP
Articles by Antonella Consiglio
Based on 10 articles published since 2010
(Why 10 articles?)
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Between 2010 and 2020, Antonella Consiglio wrote the following 10 articles about Parkinson Disease.
 
+ Citations + Abstracts
1 Review Modeling the genetic complexity of Parkinson's disease by targeted genome edition in iPS cells. 2017

Calatayud, Carles / Carola, Giulia / Consiglio, Antonella / Raya, Angel. ·Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, 3rd Floor, Av. Gran Via 199-203, 08908 Hospitalet de Llobregat (Barcelona), Spain; Institute of Biomedicine (IBUB) of the University of Barcelona (UB), 08028 Barcelona, Spain; Department of Pathology and Experimental Therapeutics, School of Medicine, University of Barcelona, 08908 Barcelona, Spain. · Institute of Biomedicine (IBUB) of the University of Barcelona (UB), 08028 Barcelona, Spain; Department of Pathology and Experimental Therapeutics, School of Medicine, University of Barcelona, 08908 Barcelona, Spain. · Institute of Biomedicine (IBUB) of the University of Barcelona (UB), 08028 Barcelona, Spain; Department of Pathology and Experimental Therapeutics, School of Medicine, University of Barcelona, 08908 Barcelona, Spain; Department of Molecular and Translational Medicine, University of Brescia and National Institute of Neuroscience, 25123 Brescia, Italy. Electronic address: aconsiglio@ibub.pcb.ub.es. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, 3rd Floor, Av. Gran Via 199-203, 08908 Hospitalet de Llobregat (Barcelona), Spain; Center 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. Electronic address: araya@cmrb.eu. ·Curr Opin Genet Dev · Pubmed #28759872.

ABSTRACT: Patient-specific iPSC are being intensively exploited as experimental disease models. Even for late-onset diseases of complex genetic influence, such as Parkinson's disease (PD), the use of iPSC-based models is beginning to provide important insights into the genetic bases of PD heritability. Here, we present an update on recently reported genetic risk factors associated with PD. We discuss how iPSC technology, combined with targeted edition of the coding or noncoding genome, can be used to address clinical observations such as incomplete penetrance, and variability in phenoconversion or age-at-onset in familial PD. Finally, we also discuss the relevance of advanced iPSC/CRISPR/Cas9 disease models to ascertain causality in genotype-to-phenotype correlation studies of sporadic PD.

2 Review Using iPS Cells toward the Understanding of Parkinson's Disease. 2015

Torrent, Roger / De Angelis Rigotti, Francesca / Dell'Era, Patrizia / Memo, Maurizio / Raya, Angel / Consiglio, Antonella. ·Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain. rtorrent@gmail.com. · Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain. fdeangelisrigotti@ibub.pcb.ub.es. · Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy. patrizia.dellera@med.unibs.it. · Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy. maurizio.memo@med.unibs.it. · Control of Stem Cell Potency Group, Institute for Bioengineering of Catalonia (IBEC), Barcelona 08028, Spain. araya@ibecbarcelona.eu. · Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. araya@ibecbarcelona.eu. · Center for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid 28029, Spain. araya@ibecbarcelona.eu. · Center of Regenerative Medicine in Barcelona, Dr. Aiguader 88, Barcelona 08003, Spain. araya@ibecbarcelona.eu. · Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Barcelona 08028, Spain. aconsiglio@ibub.pcb.ub.es. · Department of Molecular and Translational Medicine, Fibroblast Reprogramming Unit, University of Brescia, Brescia 25123, Italy. aconsiglio@ibub.pcb.ub.es. ·J Clin Med · Pubmed #26239346.

ABSTRACT: Cellular reprogramming of somatic cells to human pluripotent stem cells (iPSC) represents an efficient tool for in vitro modeling of human brain diseases and provides an innovative opportunity in the identification of new therapeutic drugs. Patient-specific iPSC can be differentiated into disease-relevant cell types, including neurons, carrying the genetic background of the donor and enabling de novo generation of human models of genetically complex disorders. Parkinson's disease (PD) is the second most common age-related progressive neurodegenerative disease, which is mainly characterized by nigrostriatal dopaminergic (DA) neuron degeneration and synaptic dysfunction. Recently, the generation of disease-specific iPSC from patients suffering from PD has unveiled a recapitulation of disease-related cell phenotypes, such as abnormal α-synuclein accumulation and alterations in autophagy machinery. The use of patient-specific iPSC has a remarkable potential to uncover novel insights of the disease pathogenesis, which in turn will open new avenues for clinical intervention. This review explores the current Parkinson's disease iPSC-based models highlighting their role in the discovery of new drugs, as well as discussing the most challenging limitations iPSC-models face today.

3 Review Induced pluripotent stem cell-based studies of Parkinson's disease: challenges and promises. 2013

Sanchez-Danes, Adriana / Benzoni, Patrizia / Memo, Maurizio / Dell'Era, Patrizia / Raya, Angel / Consiglio, Antonella. ·Institute for Biomedicine of the University of Barcelona (IBUB), Barcelona Science Park, Baldiri Reixac 15-21, 08028 Barcelona, Spain. aconsiglio@pcb.ub.es. ·CNS Neurol Disord Drug Targets · Pubmed #24040813.

ABSTRACT: A critical step in the development of effective therapeutics to treat Parkinson's disease (PD) is the identification of molecular pathogenic mechanisms underlying this chronically progressive neurodegenerative disease. However, while animal models have provided valuable information about the molecular basis of PD, the lack of faithful cellular and animal models that recapitulate human pathophysiology is delaying the development of new therapeutics. The reprogramming of somatic cells to induced pluripotent stem cells (iPSC) using delivery of defined combinations of transcription factors is a groundbreaking discovery that opens great opportunities for modeling human diseases, including PD, since iPSC can be generated from patients and differentiated into disease-relevant cell types, which would capture the patients' genetic complexity. Furthermore, human iPSC-derived neuronal models offer unprecedented access to early stages of the disease, allowing the investigation of the events that initiate the pathologic process in PD. Recently, human iPSC-derived neurons from patients with familial and sporadic PD have been generated and importantly they recapitulate some PD-related cell phenotypes, including abnormal α-synuclein accumulation in vitro, and alterations in the autophagy machinery. This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field.

4 Article Enhancing glycolysis attenuates Parkinson's disease progression in models and clinical databases. 2019

Cai, Rong / Zhang, Yu / Simmering, Jacob E / Schultz, Jordan L / Li, Yuhong / Fernandez-Carasa, Irene / Consiglio, Antonella / Raya, Angel / Polgreen, Philip M / Narayanan, Nandakumar S / Yuan, Yanpeng / Chen, Zhiguo / Su, Wenting / Han, Yanping / Zhao, Chunyue / Gao, Lifang / Ji, Xunming / Welsh, Michael J / Liu, Lei. ·Institute of Hypoxia Medicine, Xuanwu Hospital and Key Laboratory for Neurodegenerative Diseases of the Ministry of Education, and. · Center of Stroke, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, China. · State Key Laboratory of Membrane Biology, School of Life Sciences, Peking University, Beijing, China. · Department of Internal Medicine and. · Departments of Pharmaceutical Care and Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat and Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain. · Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy. · Center of Regenerative Medicine in Barcelona (CMRB) and Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain. · Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain. · Departments of Internal Medicine and Epidemiology and. · Department of Neurology, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. · Beijing Advanced Innovation Center for Big Data-Based Precision Medicine, Beihang University, Beijing, China. · Howard Hughes Medical Institute, Departments of Internal Medicine, Neurology, and Molecular Physiology and Biophysics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA. ·J Clin Invest · Pubmed #31524631.

ABSTRACT: Parkinson's disease (PD) is a common neurodegenerative disease that lacks therapies to prevent progressive neurodegeneration. Impaired energy metabolism and reduced ATP levels are common features of PD. Previous studies revealed that terazosin (TZ) enhances the activity of phosphoglycerate kinase 1 (PGK1), thereby stimulating glycolysis and increasing cellular ATP levels. Therefore, we asked whether enhancement of PGK1 activity would change the course of PD. In toxin-induced and genetic PD models in mice, rats, flies, and induced pluripotent stem cells, TZ increased brain ATP levels and slowed or prevented neuron loss. The drug increased dopamine levels and partially restored motor function. Because TZ is prescribed clinically, we also interrogated 2 distinct human databases. We found slower disease progression, decreased PD-related complications, and a reduced frequency of PD diagnoses in individuals taking TZ and related drugs. These findings suggest that enhancing PGK1 activity and increasing glycolysis may slow neurodegeneration in PD.

5 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.

6 Article Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson's Disease. 2019

di Domenico, Angelique / Carola, Giulia / Calatayud, Carles / Pons-Espinal, Meritxell / Muñoz, Juan Pablo / Richaud-Patin, Yvonne / Fernandez-Carasa, Irene / Gut, Marta / Faella, Armida / Parameswaran, Janani / Soriano, Jordi / Ferrer, Isidro / Tolosa, Eduardo / Zorzano, Antonio / Cuervo, Ana Maria / Raya, Angel / Consiglio, Antonella. ·Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain. · Institute for Research in Biomedicine (IRB), Carrer Baldiri Reixac 10, Barcelona 08028, Spain. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain. · Centre Nacional d'Anàlisi Genòmica (CNAG-CRG), Parc Científic de Barcelona, Barcelona 08028, Spain. · Departament de Física de la Matèria Condensada, Universitat de Barcelona, Barcelona 08028, Spain; Universitat de Barcelona Institute of Complex Systems (UBICS), Barcelona 08028, Spain. · Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain. · Centre for Networked Biomedical Research on Neurodegenerative Diseases (CIBERNED), Madrid 28049, Spain; Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomédiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona 08036, Spain. · Albert Einstein College of Medicine, Bronx, NY 10461, USA. · Center of Regenerative Medicine in Barcelona (CMRB), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona 08908, Spain; Centre for Networked Biomedical Research on Bioengineering, Biomaterials, and Nanomedicine (CIBER-BBN), Madrid 28029, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona 08010, Spain. Electronic address: araya@cmrb.eu. · Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Barcelona 08908, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona 08028, Spain; Department of Molecular and Translational Medicine, University of Brescia, Brescia 25121, Italy. Electronic address: consiglio@ub.edu. ·Stem Cell Reports · Pubmed #30639209.

ABSTRACT: Parkinson's disease (PD) is associated with the degeneration of ventral midbrain dopaminergic neurons (vmDAns) and the accumulation of toxic α-synuclein. A non-cell-autonomous contribution, in particular of astrocytes, during PD pathogenesis has been suggested by observational studies, but remains to be experimentally tested. Here, we generated induced pluripotent stem cell-derived astrocytes and neurons from familial mutant LRRK2 G2019S PD patients and healthy individuals. Upon co-culture on top of PD astrocytes, control vmDAns displayed morphological signs of neurodegeneration and abnormal, astrocyte-derived α-synuclein accumulation. Conversely, control astrocytes partially prevented the appearance of disease-related phenotypes in PD vmDAns. We additionally identified dysfunctional chaperone-mediated autophagy (CMA), impaired macroautophagy, and progressive α-synuclein accumulation in PD astrocytes. Finally, chemical enhancement of CMA protected PD astrocytes and vmDAns via the clearance of α-synuclein accumulation. Our findings unveil a crucial non-cell-autonomous contribution of astrocytes during PD pathogenesis, and open the path to exploring novel therapeutic strategies aimed at blocking the pathogenic cross talk between neurons and glial cells.

7 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.

8 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.

9 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.

10 Article Disease-specific phenotypes in dopamine neurons from human iPS-based models of genetic and sporadic Parkinson's disease. 2012

Sánchez-Danés, Adriana / Richaud-Patin, Yvonne / Carballo-Carbajal, Iria / Jiménez-Delgado, Senda / Caig, Carles / Mora, Sergio / Di Guglielmo, Claudia / Ezquerra, Mario / Patel, Bindiben / Giralt, Albert / Canals, Josep M / Memo, Maurizio / Alberch, Jordi / López-Barneo, José / Vila, Miquel / Cuervo, Ana Maria / Tolosa, Eduard / Consiglio, Antonella / Raya, Angel. ·Institute for Biomedicine (IBUB), University of Barcelona, Barcelona, Spain. ·EMBO Mol Med · Pubmed #22407749.

ABSTRACT: Induced pluripotent stem cells (iPSC) offer an unprecedented opportunity to model human disease in relevant cell types, but it is unclear whether they could successfully model age-related diseases such as Parkinson's disease (PD). Here, we generated iPSC lines from seven patients with idiopathic PD (ID-PD), four patients with familial PD associated to the G2019S mutation in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene (LRRK2-PD) and four age- and sex-matched healthy individuals (Ctrl). Over long-time culture, dopaminergic neurons (DAn) differentiated from either ID-PD- or LRRK2-PD-iPSC showed morphological alterations, including reduced numbers of neurites and neurite arborization, as well as accumulation of autophagic vacuoles, which were not evident in DAn differentiated from Ctrl-iPSC. Further induction of autophagy and/or inhibition of lysosomal proteolysis greatly exacerbated the DAn morphological alterations, indicating autophagic compromise in DAn from ID-PD- and LRRK2-PD-iPSC, which we demonstrate occurs at the level of autophagosome clearance. Our study provides an iPSC-based in vitro model that captures the patients' genetic complexity and allows investigation of the pathogenesis of both sporadic and familial PD cases in a disease-relevant cell type.