{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T23:27:23Z","timestamp":1791502043973,"version":"4.3.4"},"reference-count":81,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2013,4,11]],"date-time":"2013-04-11T00:00:00Z","timestamp":1365638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Movement Disorders"],"published-print":{"date-parts":[[2013,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Impairment of autophagy\u2010lysosomal 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\u2010related neurodegeneration. In addition, PD\u2010linked mutations and post\u2010translational modifications of \u03b1\u2010synuclein impair its own lysosomal\u2010mediated degradation, thereby contributing to its accumulation and aggregation. Furthermore, other PD\u2010related genes, such as leucine\u2010rich repeat kinase\u20102 (\n                    <jats:italic>LRRK2<\/jats:italic>\n                    ),\n                    <jats:italic>parkin<\/jats:italic>\n                    , and phosphatase and tensin homolog (PTEN)\u2010induced putative kinase 1 (\n                    <jats:italic>PINK1<\/jats:italic>\n                    ), have been mechanistically linked to alterations in ALPs. Conversely, mutations in lysosomal\u2010related genes, such as glucocerebrosidase (\n                    <jats:italic>GBA<\/jats:italic>\n                    ) and lysosomal type 5 P\u2010type ATPase (\n                    <jats:italic>ATP13A2<\/jats:italic>\n                    ), have been linked to PD. New data offer mechanistic molecular evidence for such a connection, unraveling a causal link between lysosomal impairment, \u03b1\u2010synuclein accumulation, and neurotoxicity. First, PD\u2010related GBA deficiency\/mutations initiate a positive feedback loop in which reduced lysosomal function leads to \u03b1\u2010synuclein accumulation, which, in turn, further decreases lysosomal GBA activity by impairing the trafficking of GBA from the endoplasmic reticulum\u2010Golgi to lysosomes, leading to neurodegeneration. Second, PD\u2010related mutations\/deficiency in the\n                    <jats:italic>ATP13A2<\/jats:italic>\n                    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 \u03b1\u2010synuclein 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\u2010modifying therapeutic strategies aimed at restoring lysosomal levels and function. \u00a9 2013\n                    <jats:italic>Movement<\/jats:italic>\n                    Disorder Society\n                  <\/jats:p>","DOI":"10.1002\/mds.25462","type":"journal-article","created":{"date-parts":[[2013,4,11]],"date-time":"2013-04-11T12:43:14Z","timestamp":1365684194000},"page":"725-732","source":"Crossref","is-referenced-by-count":331,"title":["Lysosomal impairment in Parkinson's disease"],"prefix":"10.1002","volume":"28","author":[{"given":"Benjamin","family":"Dehay","sequence":"first","affiliation":[{"name":"Institute of Neurodegenerative Diseases University of Bordeaux Segalen Centre National de la Recherche Scientifique Unit\u00e9 Mixte de Recherche 5293 Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Martinez\u2010Vicente","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group Vall d'Hebron Research Institute Centro Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Neurodegenerativas Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy A.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences The University of Alabama Tuscaloosa Alabama USA"},{"name":"Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim A.","family":"Caldwell","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences The University of Alabama Tuscaloosa Alabama USA"},{"name":"Departments of Neurology and Neurobiology, Center for Neurodegeneration and Experimental Therapeutics University of Alabama at Birmingham Birmingham Alabama USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenyue","family":"Yue","sequence":"additional","affiliation":[{"name":"Departments of Neurology and Neuroscience Friedman Brain Institute Icahn School of Medicine at Mount Sinai New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Cookson","sequence":"additional","affiliation":[{"name":"Cell Biology and Gene Expression Section, Laboratory of Neurogenetics National Institute of Health Bethesda Maryland USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Klein","sequence":"additional","affiliation":[{"name":"Institute of Neurogenetics University of Lubeck Lubeck Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miquel","family":"Vila","sequence":"additional","affiliation":[{"name":"Neurodegenerative Diseases Research Group Vall d'Hebron Research Institute Centro Investigaci\u00f3n Biom\u00e9dica en Red Enfermedades Neurodegenerativas Barcelona Spain"},{"name":"Department of Biochemistry and Molecular Biology Autonomous University of Barcelona Bellaterra Barcelona Spain"},{"name":"Catalan Institution for Research and Advanced Studies Barcelona Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erwan","family":"Bezard","sequence":"additional","affiliation":[{"name":"Institute of Neurodegenerative Diseases University of Bordeaux Segalen Centre National de la Recherche Scientifique Unit\u00e9 Mixte de Recherche 5293 Bordeaux 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