Lysosomal impairment in Parkinson's disease.
Benjamin Dehay,Marta Martinez-Vicente,Guy A. Caldwell,Kim A. Caldwell,Zhenyue Yue,Mark R. Cookson,Christine Klein,Miquel Vila,Erwan Bezard +8 more
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TLDR
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.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.read more
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The SH-SY5Y cell line in Parkinson's disease research: a systematic review
TL;DR: An overview of the cell source, culture conditions, differentiation protocols, methods/approaches used to mimic PD and the preclinical validation of the SH-SY5Y findings by employing alternative cellular and animal models is described.
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The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration.
TL;DR: The endosomal-lysosomal system is emerging as a central player in a host of neurodegenerative diseases, demonstrating potential roles which are likely to be revealed in pathogenesis and for viable therapeutic strategies.
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Disorders of lysosomal acidification—The emerging role of v-ATPase in aging and neurodegenerative disease
TL;DR: The unique vulnerability of neurons to persistent low level lysosomal dysfunction is discussed and recent clinical and experimental studies that link dysfunction of the v-ATPase complex to neurodegenerative diseases across the age spectrum are reviewed.
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Lysosomes as a therapeutic target.
TL;DR: This Review critically analyses progress and opportunities for therapeutically targeting lysosomal proteins and processes, particularly with small molecules and peptide drugs in autoimmune disorders and neurodegenerative diseases.
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At the end of the autophagic road: an emerging understanding of lysosomal functions in autophagy
Han-Ming Shen,Noboru Mizushima +1 more
TL;DR: New discoveries include connections between autophagy and lysosomal biogenesis, activation, reformation, and turnover, as well as the identification of an autophagosomal SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) protein in control of Autophagosome-lysosome fusion.
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