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Parkinson Disease: HELP
Articles by Mark R. Cookson
Based on 70 articles published since 2010
(Why 70 articles?)
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Between 2010 and 2020, Mark R. Cookson wrote the following 70 articles about Parkinson Disease.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Editorial Identification of bona-fide LRRK2 kinase substrates. 2016

West, Andrew B / Cookson, Mark R. ·Center for Neurodegeneration and Experimental Therapeutics, Department of Neurology, The University of Alabama at Birmingham, Birmingham, Alabama, USA. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. ·Mov Disord · Pubmed #27126091.

ABSTRACT: -- No abstract --

2 Editorial Lardy brains make Parkinson's disease mice worse. 2014

Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA. ·J Neurochem · Pubmed #25142063.

ABSTRACT: -- No abstract --

3 Editorial Parkinson disease, cancer, and LRRK2: causation or association? 2012

Bandmann, Oliver / Cookson, Mark R. · ·Neurology · Pubmed #22323745.

ABSTRACT: -- No abstract --

4 Editorial Editorial hot topic: drug targets in Parkinson's disease: where are we and where should we go?]. 2011

Cookson, Mark R. · ·CNS Neurol Disord Drug Targets · Pubmed #21838673.

ABSTRACT: -- No abstract --

5 Editorial Astrocytes in Parkinson's disease and DJ-1. 2011

Hauser, David N / Cookson, Mark R. · ·J Neurochem · Pubmed #21413989.

ABSTRACT: -- No abstract --

6 Review Glial phagocytic clearance in Parkinson's disease. 2019

Tremblay, Marie-Eve / Cookson, Mark R / Civiero, Laura. ·Axe Neurosciences, Centre de Recherche du CHU de Québec, Université Laval, Quebec, QC, Canada. · Département de Médecine Moléculaire, Faculté de Médecine, Université Laval, Quebec, QC, Canada. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Department of Biology, University of Padova, Via Ugo Bassi 58/B, 35131, Padova, Italy. laura.civiero@unipd.it. ·Mol Neurodegener · Pubmed #30953527.

ABSTRACT: An emerging picture suggests that glial cells' loss of beneficial roles or gain of toxic functions can contribute to neurodegenerative conditions. Among glial cells, microglia and astrocytes have been shown to play phagocytic roles by engulfing synapses, apoptotic cells, cell debris, and released toxic proteins. As pathogenic protein accumulation is a key feature in Parkinson's disease (PD), compromised phagocytic clearance might participate in PD pathogenesis. In contrast, enhanced, uncontrolled and potentially toxic glial clearance capacity could contribute to synaptic degeneration. Here, we summarize the current knowledge of the molecular mechanisms underlying microglial and astrocytic phagocytosis, focusing on the possible implication of phagocytic dysfunction in neuronal degeneration. Several endo-lysosomal proteins displaying genetic variants in PD are highly expressed by microglia and astrocytes. We also present the evidence that lysosomal defects can affect phagocytic clearance and discuss the therapeutic relevance of restoring or enhancing lysosomal function in PD.

7 Review LRRK2 links genetic and sporadic Parkinson's disease. 2019

Kluss, Jillian H / Mamais, Adamantios / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bldg. 35, 35 Convent Drive, Bethesda, MD 20892-3707, U.S.A. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bldg. 35, 35 Convent Drive, Bethesda, MD 20892-3707, U.S.A. cookson@mail.nih.gov. ·Biochem Soc Trans · Pubmed #30837320.

ABSTRACT: The past two decades in research has revealed the importance of leucine-rich repeat kinase 2 (LRRK2) in both monogenic and sporadic forms of Parkinson's disease (PD). In families, mutations in LRRK2 can cause PD with age-dependent but variable penetrance and genome-wide association studies have found variants of the gene that are risk factors for sporadic PD. Functional studies have suggested that the common mechanism that links all disease-associated variants is that they increase LRRK2 kinase activity, albeit in different ways. Here, we will discuss the roles of LRRK2 in areas of inflammation and vesicular trafficking in the context of monogenic and sporadic PD. We will also provide a hypothetical model that links inflammation and vesicular trafficking together in an effort to outline how these pathways might interact and eventually lead to neuronal cell death. We will also highlight the translational potential of LRRK2-specific kinase inhibitors for the treatment of PD.

8 Review The role of monogenic genes in idiopathic Parkinson's disease. 2019

Reed, Xylena / Bandrés-Ciga, Sara / Blauwendraat, Cornelis / Cookson, Mark R. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: cookson@mail.nih.gov. ·Neurobiol Dis · Pubmed #30448284.

ABSTRACT: In the past two decades, mutations in multiple genes have been linked to autosomal dominant or recessive forms of monogenic Parkinson's disease (PD). Collectively, these monogenic (often familial) cases account for less than 5% of all PD, the majority being apparently sporadic cases. More recently, large-scale genome-wide association studies have identified over 40 loci that increase risk of PD. Importantly, there is overlap between monogenic and sporadic PD genes, particularly for the loci that contain the genes SNCA and LRRK2, which are mutated in monogenic dominant PD. There have also been reports of idiopathic PD cases with heterozygous variants in autosomal recessive genes suggesting that these mutations may increase risk of PD. These observations suggest that monogenic and idiopathic PD may have shared pathogenic mechanisms. Here, we focus mainly on the role of monogenic PD genes that represent pleomorphic risk loci for idiopathic PD. We also discuss the functional mechanisms that may play a role in increasing risk of disease in both monogenic and idiopathic forms.

9 Review Finding useful biomarkers for Parkinson's disease. 2018

Chen-Plotkin, Alice S / Albin, Roger / Alcalay, Roy / Babcock, Debra / Bajaj, Vikram / Bowman, Dubois / Buko, Alex / Cedarbaum, Jesse / Chelsky, Daniel / Cookson, Mark R / Dawson, Ted M / Dewey, Richard / Foroud, Tatiana / Frasier, Mark / German, Dwight / Gwinn, Katrina / Huang, Xuemei / Kopil, Catherine / Kremer, Thomas / Lasch, Shirley / Marek, Ken / Marto, Jarrod A / Merchant, Kalpana / Mollenhauer, Brit / Naito, Anna / Potashkin, Judith / Reimer, Alyssa / Rosenthal, Liana S / Saunders-Pullman, Rachel / Scherzer, Clemens R / Sherer, Todd / Singleton, Andrew / Sutherland, Margaret / Thiele, Ines / van der Brug, Marcel / Van Keuren-Jensen, Kendall / Vaillancourt, David / Walt, David / West, Andrew / Zhang, Jing. ·Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. chenplot@pennmedicine.upenn.edu. · Neurology Service and GRECC, VAAHS, Ann Arbor, MI 48105, USA. · Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA. · Department of Neurology, Columbia University Medical Center, New York, NY 10032, USA. · National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20824, USA. · Verily/Google Life Sciences, South San Francisco, CA 94080, USA. · Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, NY 10032, USA. · Human Metabolome Technology-America, Boston, MA 02134, USA. · Biogen, Cambridge, MA 02142, USA. · Caprion Biosciences, Montreal, Quebec H2X 3Y7, Canada. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Aging, National Institutes of Health, Bethesda, MD 20892, USA. · Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. · The Michael J. Fox Foundation for Parkinson's Research, New York, NY 10163, USA. · Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. · Department of Neurology, Penn State University-Hershey Medical Center, Hershey, PA 17033, USA. · Pharmaceutical Research and Early Development, NORD Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., 4070 Basel, Switzerland. · Institute for Neurodegenerative Disorders, New Haven, CT 06510, USA. · Departments of Cancer Biology and Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Blais Proteomics Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA. · Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02215, USA. · Chaperone Therapeutics, Portland, OR 97229, USA. · Paracelsus-Elena-Klinik, 34128 Kassel, Germany. · University Medical Center, 37075 Goettingen, Germany. · Department of Cellular and Molecular Pharmacology, Chicago Medical School, Rosalind Franklin University of Medicine and Science, Chicago, IL 60064, USA. · Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA. · Department of Neurology, Mount Sinai Beth Israel, Icahn School of Medicine at Mount Sinai, New York, NY 10003, USA. · Center for Advanced Parkinson's Disease Research and Precision Neurology Program, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. · Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892, USA. · Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Luxembourg, Luxembourg. · Genentech, San Francisco, CA 94080, USA. · Neurogenomics Division, Translational Genomics Research Institute, Phoenix, AZ 85004, USA. · Department of Applied Physiology, Biomedical Engineering, and Neurology, University of Florida, Gainesville, FL 32611, USA. · Department of Neurology, University of Alabama, Birmingham, AL 35233, USA. · Department of Pathology, University of Washington, Seattle, WA 98195, USA. ·Sci Transl Med · Pubmed #30111645.

ABSTRACT: The recent advent of an "ecosystem" of shared biofluid sample biorepositories and data sets will focus biomarker efforts in Parkinson's disease, boosting the therapeutic development pipeline and enabling translation with real-world impact.

10 Review The LRRK2 signalling system. 2018

Price, Alice / Manzoni, Claudia / Cookson, Mark R / Lewis, Patrick A. ·School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. · Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building. 35, 35 Convent Drive, Bethesda, MD, 20892, USA. · School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK. p.a.lewis@reading.ac.uk. · Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. p.a.lewis@reading.ac.uk. ·Cell Tissue Res · Pubmed #29308544.

ABSTRACT: The LRRK2 gene is a major contributor to genetic risk for Parkinson's disease and understanding the biology of the leucine-rich repeat kinase 2 (LRRK2, the protein product of this gene) is an important goal in Parkinson's research. LRRK2 is a multi-domain, multi-activity enzyme and has been implicated in a wide range of signalling events within the cell. Because of the complexities of the signal transduction pathways in which LRRK2 is involved, it has been challenging to generate a clear idea as to how mutations and disease associated variants in this gene are altered in disease. Understanding the events in which LRRK2 is involved at a systems level is therefore critical to fully understand the biology and pathobiology of this protein and is the subject of this review.

11 Review Gene Linkage and Systems Biology. 2017

Cookson, Mark R. ·Laboratory of Neurogenetics, NIA, NIH. 35, Convent Drive, Bethesda, MD, 20892-3707, USA. cookson@mail.nih.gov. ·Adv Neurobiol · Pubmed #28674994.

ABSTRACT: In the past two decades it has become increasingly clear that the risk for many neurodegenerative disorders is at least partially genetic. Assignment of causality for a given gene depends on showing that a particular variant shows either segregation within a family or association with disease across a population. In terms of lifetime risk of disease, the former generally show strong effects compared to the latter. In rare, but interesting, circumstances there are genetic loci that contain different variants that encode either highly penetrant Mendelian disease but also that contribute to risk of sporadic disease. Here, we will discuss the current efforts to complete our understanding of the genetic architecture of neurodegenerative diseases of aging with a particular focus on Parkinson's disease. We will also briefly outline attempts to use systematic approaches to infer relationships between genes associated with the same diseases, which likely demonstrate that in each case there are a relatively small number of underlying biological pathways or processes that may explain pathogenesis.

12 Review The Effects of Variants in the Parkin, PINK1, and DJ-1 Genes along with Evidence for their Pathogenicity. 2017

Hauser, David N / Primiani, Christopher T / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, MD, United States. · Cell Biology and Gene Expression Section, NIA, Building 35, Room 1A116, 5 Convent Drive, MSC 3707, Bethesda, MD 20892-3707, United States. ·Curr Protein Pept Sci · Pubmed #26965687.

ABSTRACT: Early onset Parkinson's disease can be caused by variants in the PINK1, Parkin, and DJ-1 genes. Since their initial discoveries, hundreds of variants have been found in these genes that are associated with a Parkinsonian phenotype. This review will briefly discuss the functions of the protein products of the three genes, then focus on the effects that disease associated variants have on these functions. We will also discuss how experimental findings can help decide whether individual variants are pathogenic or not.

13 Review LRRK2 at the interface of autophagosomes, endosomes and lysosomes. 2016

Roosen, Dorien A / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bldg. 35, 35 Convent Drive, Bethesda, MD, 20892-3707, USA. · School of Pharmacy, University of Reading, Whiteknights, Reading, RG6 6AP, UK. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bldg. 35, 35 Convent Drive, Bethesda, MD, 20892-3707, USA. cookson@mail.nih.gov. ·Mol Neurodegener · Pubmed #27927216.

ABSTRACT: Over the past 20 years, substantial progress has been made in identifying the underlying genetics of Parkinson's disease (PD). Of the known genes, LRRK2 is a major genetic contributor to PD. However, the exact function of LRRK2 remains to be elucidated. In this review, we discuss how familial forms of PD have led us to hypothesize that alterations in endomembrane trafficking play a role in the pathobiology of PD. We will discuss the major observations that have been made to elucidate the role of LRRK2 in particular, including LRRK2 animal models and high-throughput proteomics approaches. Taken together, these studies strongly support a role of LRRK2 in vesicular dynamics. We also propose that targeting these pathways may not only be beneficial for developing therapeutics for LRRK2-driven PD, but also for other familial and sporadic cases.

14 Review Cellular functions of LRRK2 implicate vesicular trafficking pathways in Parkinson's disease. 2016

Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 35, Room 1A116, MSC3707, 35, Convent Drive, Bethesda, MD 20892-3707, USA. ·Biochem Soc Trans · Pubmed #27913668.

ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene, associated with Parkinson's disease, have been shown to affect intracellular trafficking pathways in a variety of cells and organisms. An emerging theme is that LRRK2 can bind to multiple membranous structures in cells, and several recent studies have suggested that the Rab family of small GTPases might be important in controlling the recruitment of LRRK2 to specific cellular compartments. Once localized to membranes, LRRK2 then influences downstream events, evidenced by changes in the autophagy-lysosome pathway. Here, I will discuss available evidence that supports or challenges this outline, with a specific emphasis on those aspects of LRRK2 function that have been controversial or remain to be fully clarified.

15 Review The function of orthologues of the human Parkinson's disease gene LRRK2 across species: implications for disease modelling in preclinical research. 2016

Langston, Rebekah G / Rudenko, Iakov N / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD 20892, U.S.A. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, NIA, NIH, Bethesda, MD 20892, U.S.A. cookson@mail.nih.gov. ·Biochem J · Pubmed #26811536.

ABSTRACT: In the period since LRRK2 (leucine-rich repeat kinase 2) was identified as a causal gene for late-onset autosomal dominant parkinsonism, a great deal of work has been aimed at understanding whether the LRRK2 protein might be a druggable target for Parkinson's disease (PD). As part of this effort, animal models have been developed to explore both the normal and the pathophysiological roles of LRRK2. However, LRRK2 is part of a wider family of proteins whose functions in different organisms remain poorly understood. In this review, we compare the information available on biochemical properties of LRRK2 homologues and orthologues from different species from invertebrates (e.g. Caenorhabditis elegans and Drosophila melanogaster) to mammals. We particularly discuss the mammalian LRRK2 homologue, LRRK1, and those species where there is only a single LRRK homologue, discussing examples where each of the LRRK family of proteins has distinct properties as well as those cases where there appear to be functional redundancy. We conclude that uncovering the function of LRRK2 orthologues will help to elucidate the key properties of human LRRK2 as well as to improve understanding of the suitability of different animal models for investigation of LRRK2-related PD.

16 Review Genes associated with Parkinson's disease: regulation of autophagy and beyond. 2016

Beilina, Alexandra / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, Maryland, USA. cookson@mail.nih.gov. ·J Neurochem · Pubmed #26223426.

ABSTRACT: Substantial progress has been made in the genetic basis of Parkinson's disease (PD). In particular, by identifying genes that segregate with inherited PD or show robust association with sporadic disease, and by showing the same genes are found on both lists, we have generated an outline of the cause of this condition. Here, we will discuss what those genes tell us about the underlying biology of PD. We specifically discuss the relationships between protein products of PD genes and show that common links include regulation of the autophagy-lysosome system, an important way by which cells recycle proteins and organelles. We also discuss whether all PD genes should be considered to be in the same pathway and propose that in some cases the relationships are closer, whereas in other cases the interactions are more distant and might be considered separate. Beilina and Cookson review the links between genes for Parkinson's disease (red) and the autophagy-lysosomal system. They propose the hypothesis that many of the known PD genes can be assigned to pathways that affect (I) turnover of mitochondria via mitophagy (II) turnover of several vesicular structures via macroautophagy or chaperone-mediated autophagy or (III) general lysosome function. This article is part of a special issue on Parkinson disease.

17 Review Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease. 2015

Kumaran, Ravindran / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA. · Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA cookson@mail.nih.gov. ·Hum Mol Genet · Pubmed #26101198.

ABSTRACT: In the past few years, there have been a large number of genes identified that contribute to the lifetime risk of Parkinson's disease (PD). Some genes follow a Mendelian inheritance pattern, but others are risk factors for apparently sporadic PD. Here, we will focus on those genes nominated by genome-wide association studies (GWAS) in sporadic PD, with a particular emphasis on genes that overlap between familial and sporadic disease such as those encoding a-synuclein (SNCA), tau (MAPT), and leucine-rich repeat kinase 2 (LRRK2). We will advance the view that there are likely relationships between these genes that map not only to neuronal processes, but also to neuroinflammation. We will particularly discuss evidence for a role of PD proteins in microglial activation and regulation of the autophagy-lysosome system that is dependent on microtubule transport in neurons. Thus, there are at least two non-mutually exclusive pathways that include both non-cell-autonomous and cell-autonomous mechanisms in the PD brain. Collectively, these data have highlighted the amount of progress made in understanding PD and suggest ways forward to further dissect this disorder.

18 Review LRRK2 Pathways Leading to Neurodegeneration. 2015

Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD, 20892-3707, USA, cookson@mail.nih.gov. ·Curr Neurol Neurosci Rep · Pubmed #26008812.

ABSTRACT: Mutations in LRRK2 are associated with inherited Parkinson's disease (PD) in a large number of families, and the genetic locus containing the LRRK2 gene contains a risk factor for sporadic PD. The LRRK2 protein contains several domains that suggest a role in cellular signaling, including a kinase domain. It is also clear that LRRK2 interacts, either physically or genetically, with several other important proteins implicated in PD, suggesting that LRRK2 may be a central player in the pathways that underlie parkinsonism. As such, LRRK2 has been proposed to be a plausible target for therapeutic intervention, with kinase inhibition being pursued most actively. However, there are still several fundamental aspects of LRRK2 biology and function that remain unresolved at this time. This review will focus on the key questions of normal function of LRRK2 and how this might be related to the pathophysiology of PD.

19 Review Heterogeneity of leucine-rich repeat kinase 2 mutations: genetics, mechanisms and therapeutic implications. 2014

Rudenko, Iakov N / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, 20892, USA. ·Neurotherapeutics · Pubmed #24957201.

ABSTRACT: Variation within and around the leucine-rich repeat kinase 2 (LRRK2) gene is associated with familial and sporadic Parkinson's disease (PD). Here, we discuss the prevalence of LRRK2 substitutions in different populations and their association with PD, as well as molecular and cellular mechanisms of pathologically relevant LRRK2 mutations. Kinase activation was proposed as a universal molecular mechanism for all pathogenic LRRK2 mutations, but later reports revealed heterogeneity in the effect of mutations on different activities of LRRK2. One mutation (G2019S) increases kinase activity, whereas mutations in the Ras of complex proteins (ROC)-C-terminus of ROC (COR) bidomain impair the GTPase function of LRRK2. Some risk factor variants, including G2385R in the WD40 domain, actually decrease the kinase activity of LRRK2. We suggest a model where LRRK2 mutations exert different molecular mechanisms but interfere with normal cellular function of LRRK2 at different levels of the same downstream pathway. Finally, we discuss the current state of therapeutic approaches for LRRK2-related PD.

20 Review Lysosomal impairment in Parkinson's disease. 2013

Dehay, Benjamin / Martinez-Vicente, Marta / Caldwell, Guy A / Caldwell, Kim A / Yue, Zhenyue / Cookson, Mark R / Klein, Christine / Vila, Miquel / Bezard, Erwan. ·Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Centre National de Recherche Scientifique Unité Mixte de Recherche 5293, Bordeaux, France. benjamin.dehay@u-bordeaux2.fr ·Mov Disord · Pubmed #23580333.

ABSTRACT: Impairment of autophagy-lysosomal pathways (ALPs) is increasingly regarded as a major pathogenic event in neurodegenerative diseases, including Parkinson's disease (PD). ALP alterations are observed in sporadic PD brains and in toxic and genetic rodent models of PD-related neurodegeneration. In addition, PD-linked mutations and post-translational modifications of α-synuclein impair its own lysosomal-mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD-related genes, such as leucine-rich repeat kinase-2 (LRRK2), parkin, and phosphatase and tensin homolog (PTEN)-induced putative kinase 1 (PINK1), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal-related genes, such as glucocerebrosidase (GBA) and lysosomal type 5 P-type ATPase (ATP13A2), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. First, PD-related GBA deficiency/mutations initiate a positive feedback loop in which reduced lysosomal function leads to α-synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum-Golgi to lysosomes, leading to neurodegeneration. Second, PD-related mutations/deficiency in the ATP13A2 gene lead to a general lysosomal impairment characterized by lysosomal membrane instability, impaired lysosomal acidification, decreased processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished clearance of autophagosomes, collectively contributing to α-synuclein accumulation and cell death. According to these new findings, primary lysosomal defects could potentially account for Lewy body formation and neurodegeneration in PD, laying the groundwork for the prospective development of new neuroprotective/disease-modifying therapeutic strategies aimed at restoring lysosomal levels and function.

21 Review Cellular effects of LRRK2 mutations. 2012

Cookson, Mark R. ·Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, 35 Convent Drive, Bethesda, MD 20892-3707, USA. cookson@mail.nih.gov ·Biochem Soc Trans · Pubmed #22988867.

ABSTRACT: Mutations in LRRK2 (leucine-rich repeat kinase 2) are a relatively common cause of inherited PD (Parkinson's disease), but the mechanism(s) by which mutations lead to disease are poorly understood. In the present paper, I discuss what is known about LRRK2 in cellular models, focusing specifically on assays that have been used to tease apart the effects of LRRK2 mutations on cellular phenotypes. LRRK2 expression has been suggested to cause loss of neuronal viability, although because it also has a strong effect on the length of neurites on these cells, whether this is true toxicity or not is unclear. Also, LRRK2 mutants can promote the redistribution of LRRK2 from diffuse cytosolic staining to more discrete structures, at least at high expression levels achieved in transfection experiments. The relevance of these phenotypes for PD is not yet clear, and a great deal of work is needed to understand them in more depth.

22 Review Evolution of neurodegeneration. 2012

Cookson, Mark R. ·Cell Biology and Gene Expression Unit, Laboratory of Neurogenetics, National Institute on Aging, Bethesda, MD 20892-3707, USA. cookson@mail.nih.gov ·Curr Biol · Pubmed #22975006.

ABSTRACT: A number of neurodegenerative diseases principally affect humans as they age and are characterized by the loss of specific groups of neurons in different brain regions. Although these disorders are generally sporadic, it is now clear that many of them have a substantial genetic component. As genes are the raw material with which evolution works, we might benefit from understanding these genes in an evolutionary framework. Here, I will discuss how we can understand whether evolution has shaped genes involved in neurodegeneration and the implications for practical issues, such as our choice of model systems for studying these diseases, and more theoretical concerns, such as the level of selection against these phenotypes.

23 Review Parkinsonism due to mutations in PINK1, parkin, and DJ-1 and oxidative stress and mitochondrial pathways. 2012

Cookson, Mark R. ·Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA. cookson@mail.nih.gov ·Cold Spring Harb Perspect Med · Pubmed #22951446.

ABSTRACT: Three genes have been identified that cause, in humans, autosomally inherited parkinsonism. These are PARK2, encoding the E3 ubiquitin ligase parkin; PINK1, a mitochondrial kinase; and PARK7, which codes for the protein DJ-1. In several experimental systems, it has been shown that all three proteins impact mitochondrial function and/or oxidative stress responses. These are probably related because mitochondria produce oxidative stress in neurons. Moreover, it is clear that there are relationships between these genes, with a single pathway linking PINK1 and parkin and a parallel relationship with DJ-1. Work in progress in the field is aimed at understanding these relationships in more depth.

24 Review Is inhibition of kinase activity the only therapeutic strategy for LRRK2-associated Parkinson's disease? 2012

Rudenko, Iakov N / Chia, Ruth / Cookson, Mark R. ·Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, 35 Convent Drive, Room 1A-116, Bethesda, MD 20892-3707, USA. ·BMC Med · Pubmed #22361010.

ABSTRACT: Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial Parkinson's disease (PD). Variation around the LRRK2 locus also contributes to the risk of sporadic PD. The LRRK2 protein contains a central catalytic region, and pathogenic mutations cluster in the Ras of complex protein C terminus of Ras of complex protein (mutations N1437H, R1441G/C and Y1699C) and kinase (G2019S and I2020T) domains. Much attention has been focused on the kinase domain, because kinase-dead versions of mutant LRRK2 are less toxic than kinase-active versions of the same proteins. Furthermore, kinase inhibitors may be able to mimic this effect in mouse models, although the currently tested inhibitors are not completely specific. In this review, we discuss the recent progress in the development of specific LRRK2 kinase inhibitors. We also discuss non-kinase-based therapeutic strategies for LRRK2-associated PD as it is possible that different approaches may be needed for different mutations.

25 Review Gene expression in the Parkinson's disease brain. 2012

Lewis, Patrick A / Cookson, Mark R. ·Department of Molecular Neuroscience, UCL Institute of Neurology, London, United Kingdom. patrick.lewis@ucl.ac.uk ·Brain Res Bull · Pubmed #22173063.

ABSTRACT: The study of gene expression has undergone a transformation in the past decade as the benefits of the sequencing of the human genome have made themselves felt. Increasingly, genome wide approaches are being applied to the analysis of gene expression in human disease as a route to understanding the underlying pathogenic mechanisms. In this review, we will summarise current state of gene expression studies of the brain in Parkinson's disease, and examine how these techniques can be used to gain an insight into aetiology of this devastating disorder.

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