Lysosomal impairment in Parkinson's disease

Authors

  • Benjamin Dehay PhD,

    Corresponding author
    1. Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Bordeaux, France
    • Correspondence to: Dr. B. Dehay, CNRS UMR 5293, IMN, Université Bordeaux Segalen, 146 rue Léo Saignat, 33076 Bordeaux Cedex, France; benjamin.dehay@u-bordeaux2.fr

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  • Marta Martinez-Vicente PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
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  • Guy A. Caldwell PhD,

    1. Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
    2. Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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  • Kim A. Caldwell PhD,

    1. Department of Biological Sciences, The University of Alabama, Tuscaloosa, Alabama, USA
    2. Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, Alabama, USA
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  • Zhenyue Yue PhD,

    1. Departments of Neurology and Neuroscience, Friedman Brain Institute, New York, New York, USA
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  • Mark R. Cookson PhD,

    1. Cell Biology and Gene Expression Section, Laboratory of Neurogenetics, National Institute of Health, Bethesda, Maryland, USA
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  • Christine Klein MD, PhD,

    1. Institute of Neurogenetics, University of Lubeck, Lubeck, Germany
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  • Miquel Vila MD, PhD,

    1. Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute, Barcelona, Spain
    2. Department of Biochemistry and Molecular Biology, Autonomous University of Barcelona, Barcelona, Spain
    3. Catalan Institution for Research and Advanced Studies, Barcelona, Spain
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  • Erwan Bezard PhD

    1. Institute of Neurodegenerative Diseases, University of Bordeaux Segalen, Bordeaux, France
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  • Funding Agencies: This work was supported by a Marie Curie Reintegration Grant from the European Commission (FP7-PEOPLE-2009-ERG256303; to B.D.); by a Fondation pour la Recherche Médicale grant (to B.D.), by Agence Nationale de la Recherche grants (ANR-08-MNP-018; ANR-07-MNP-Trafinlid; to E.B.); by the Volkswagen Foundation, the Hermann and Lilly Schilling Foundation, and MEFOPA (FP7) (to C.K.); by Fondo de Investigación Sanitaria-Instituto de Salud Carlos III, Spain (to M.V. and M.M.-V.); by Ministerio de Investigación, Desarrollo e Inovación, Spain (to M.M.-V); and by US National Institutes of Health, National Institute of Neurological Disorders and Stroke grants (R01NS060123, NS060809, RNS055683) and the Michael J. Fox Foundation (to Z.Y.). This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Institute on Aging (to M.R.C.) and by National Institutes of Health grant 1R15NS075684 (to G.A.C.)

  • Relevant conflicts of interest/financial disclosures: EB has equity stake in Motac holding Ltd. (Manchester, UK), receives consultancy payments from Motac Neuroscience Ltd. (Manchester, UK), has received grants from the Agence Nationale de la Recherche (France), the Michael J. Fox Foundation for Parkinson Research (USA), the European Commission and is a member of the scientific advisory board of the Michael J. Fox Foundation for Parkinson Research (USA) and of the France Parkinson association. CK is a member of the editorial board of “Neurology” and has served as editor of the “Continuum Issue Neurogenetics 2008” and as faculty at the Annual Meetings of the American Academy of Neurology since 2004. CK is a consultant to Centogene and received honoraria for speaking from Boehringer Ingelheim and Orion Pharma. CK is the recipient of a career development award from the Hermann and Lilly Schilling Foundation. CK is funded by the Volkswagen Foundation, the Deutsche Forschungsgemeinschaft, the Possehl Foundation and received institutional support from the University of Luebeck for genetics research. All other authors have nothing to report.

  • Full financial disclosures and author roles may be found in the online version of this article.

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. © 2013 Movement Disorder Society

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