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.

DNAJC13 mutations in Parkinson disease

“…Interestingly, LRRK2, in which mutations have been linked to late-onset PD (3,8), also co-immunoprecipitates with VPS35 (22). LRRK2 has a major role in autophagy (23), and genetic linkage and biological data have recently converged to nominate lysosomal impairment as a unifying molecular theme in early onset parkinsonism with LB pathology (24). However, in neurons LRRK2 plays a role in trans-Golgi protein sorting (25), morphogenesis (22) and synaptic endocytosis (26).…”

Glucocerebrosidase mutations and the pathogenesis of Parkinson disease

“…the neurological manifestations of GD. Enhancing GCase activity using PC and improving lysosomal function therefore holds particular relevance for those with GD, but could also be significant for those with PD where the impairment of lysosomal pathways is increasingly viewed as a major pathogenic event (Dehay et al, 2013) and the ability to modulate GCase activity has important therapeutic implications .…”

“…The level of intracellular SNCA is critical for the onset of neurodegeneration with LBs and dependent, to a large extent, on degradation via the lysosomal autophagy pathway. Therefore, impairment of lysosomal pathways is increasingly viewed as a major pathogenic event and unifying theme in PD (Dehay et al, 2013). Depletion of GCase may result in the toxic accumulation of insoluble SNCA within lysosomes, compromise lysosomal protein degradation, and promote a bidirectional feedback loop in which SNCA accumulates and causes a selfpropagating disease (Mazzulli et al, 2011;; Gegg et al, 2012).…”

“…The discovery of an association of the GBA mutation with PD (Sidransky et al, 2009a) has proved an important development for research on the pathogenesis of PD, and has provided support for increasing evidence that lysosomal pathways are implicated in PD (Dehay et al, 2013).…”

TMBIM6 (transmembrane BAX inhibitor motif containing 6) enhances autophagy and reduces renal dysfunction in a cyclosporine A-induced nephrotoxicity model

“…Lysosomal activity is important for the autophagy degradation process, 25,26 and we recently showed that TMBIM6 enhances lysosomal activity in other cell models. 22,23 Based on these findings, we next tested TMBIM6-related lysosomal activity in CsAtreated cells.…”