Lysosomal impairment in Parkinson's disease.

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