Lysosomal impairment in Parkinson's disease.
Identifieur interne : 000730 ( PubMed/Corpus ); précédent : 000729; suivant : 000731Lysosomal impairment in Parkinson's disease.
Auteurs : Benjamin Dehay ; Marta Martinez-Vicente ; Guy A. Caldwell ; Kim A. Caldwell ; Zhenyue Yue ; Mark R. Cookson ; Christine Klein ; Miquel Vila ; Erwan BezardSource :
- Movement disorders : official journal of the Movement Disorder Society [ 1531-8257 ] ; 2013.
English descriptors
- KwdEn :
- Animals, Autophagy, Gaucher Disease (complications), Gaucher Disease (genetics), Gaucher Disease (pathology), Glucosylceramidase (genetics), Glucosylceramidase (metabolism), Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Lysosomes (metabolism), Lysosomes (pathology), Parkinson Disease (complications), Parkinson Disease (genetics), Parkinson Disease (pathology), Protein Kinases (genetics), Protein Kinases (metabolism), Protein-Serine-Threonine Kinases (genetics), Proton-Translocating ATPases (genetics), Signal Transduction (physiology).
- MESH :
- chemical , genetics : Glucosylceramidase, Protein Kinases, Protein-Serine-Threonine Kinases, Proton-Translocating ATPases.
- complications : Gaucher Disease, Parkinson Disease.
- genetics : Gaucher Disease, Parkinson Disease.
- chemical , metabolism : Glucosylceramidase, Lysosomes, Protein Kinases.
- pathology : Gaucher Disease, Lysosomes, Parkinson Disease.
- physiology : Signal Transduction.
- Animals, Autophagy, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2.
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.
DOI: 10.1002/mds.25462
PubMed: 23580333
Links to Exploration step
pubmed:23580333Le document en format XML
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<front><div type="abstract" xml:lang="en">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.</div>
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