title: Lysosomal impairment in Parkinson's disease.
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.
authors.affiliation: 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
authors.forename: Benjamin
authors.initials: B
authors.lastname: Dehay
authors.forename: Marta
authors.initials: M
authors.lastname: Martinez-Vicente
authors.forename: Guy A
authors.initials: GA
authors.lastname: Caldwell
authors.forename: Kim A
authors.initials: KA
authors.lastname: Caldwell
authors.forename: Zhenyue
authors.initials: Z
authors.lastname: Yue
authors.forename: Mark R
authors.initials: MR
authors.lastname: Cookson
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.forename: Miquel
authors.initials: M
authors.lastname: Vila
authors.forename: Erwan
authors.initials: E
authors.lastname: Bezard
mesh_terms: D000818:Animals; D001343:Autophagy; D005776:Gaucher Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008247:Lysosomes / Q000378:metabolism / Q000473:pathology*; D010300:Parkinson Disease / Q000150:complications / Q000235:genetics / Q000473:pathology*; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D006180:Proton-Translocating ATPases / Q000235:genetics; D015398:Signal Transduction / Q000502:physiology; D000099202:PTEN-Induced Putative Kinase
chemical_list: D005962:Glucosylceramidase; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; D006180:Proton-Translocating ATPases; D000099202:PTEN-Induced Putative Kinase; C514983:ATP13A2 protein, human; C495280:LRRK2 protein, human