Journal
FRONTIERS IN NEUROLOGY
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fneur.2021.681369
Keywords
lysosome; alpha-synuclein; LRRK2; VPS35; GBA
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Funding
- JSPS KAKENHI Grant [19K07816]
- Grants-in-Aid for Scientific Research [19K07816] Funding Source: KAKEN
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Genetic studies have identified pathogenic gene mutations in hereditary Parkinson's disease (PD) and genetic variants influencing PD susceptibility in sporadic PD. Both types of PD are associated with alpha-synuclein and LRRK2, with lysosomal functions playing a critical role in PD pathogenesis. Targeting lysosomal activation may be a possible strategy for treating neurodegeneration associated with PD.
Previous genetic studies on hereditary Parkinson's disease (PD) have identified a set of pathogenic gene mutations that have strong impacts on the pathogenicity of PD. In addition, genome-wide association studies (GWAS) targeted to sporadic PD have nominated an increasing number of genetic variants that influence PD susceptibility. Although the clinical and pathological characteristics in hereditary PD are not identical to those in sporadic PD, alpha-synuclein, and LRRK2 are definitely associated with both types of PD, with LRRK2 mutations being the most frequent cause of autosomal-dominant PD. On the other hand, a significant portion of risk genes identified from GWAS have been associated with lysosomal functions, pointing to a critical role of lysosomes in PD pathogenesis. Experimental studies have suggested that the maintenance or upregulation of lysosomal activity may protect against neuronal dysfunction or degeneration. Here we focus on the roles of representative PD gene products that are implicated in lysosomal pathway, namely LRRK2, VPS35, ATP13A2, and glucocerebrosidase, and provide an overview of their disease-associated functions as well as their cooperative actions in the pathogenesis of PD, based on the evidence from cellular and animal models. We also discuss future perspectives of targeting lysosomal activation as a possible strategy to treat neurodegeneration.
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