Abstract
Chaperone-mediated autophagy (CMA) selectively delivers cytosolic proteins with an exposed CMA-targeting motif to lysosomes for degradation and plays an important role in protein quality control and cellular homeostasis. A growing body of evidence supports the hypothesis that CMA dysfunction may be involved in the pathogenic process of neurodegenerative diseases. Both down-regulation and compensatory up-regulation in CMA activities have been observed in association with neurodegenerative conditions. Recent studies have revealed several new mechanisms by which CMA function may be involved in the regulation of factors critical for neuronal viability and homeostasis. Here, we summarize these recent advances in the understanding of the relationship between CMA dysfunction and neurodegeneration and discuss the therapeutic potential of targeting CMA in the treatment of neurodegenerative diseases.
Highlights
Based on delivery mechanisms of cargo destined for the lysosomes, autophagy can be classified into three types, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [1]
Once forming insoluble inclusions, they are much more resistant to CMA-mediated degradation. These aggregates may often exert a “clogging or blockage effect” at the lysosomal membrane, becoming toxic by inhibiting the CMA-mediated degradation of other cytosolic substrate proteins [51,55]. It is not clear whether CMA dysfunction may contribute to the initial formation of insoluble inclusions, it is quite possible that the “blockage effect” on CMA may exacerbate the formation of inclusion bodies by increasing misfolded protein concentrations in the cytoplasm
Summary and perspective In summary, the identification of selective degradation of proteins relevant to neuronal survival and stress via CMA has expanded the repertoire of cellular mechanisms by which CMA may be involved in the pathogenesis of neurodegeneration
Summary
Based on delivery mechanisms of cargo destined for the lysosomes, autophagy can be classified into three types, macroautophagy, microautophagy, and chaperone-mediated autophagy (CMA) [1]. These aggregates may often exert a “clogging or blockage effect” at the lysosomal membrane, becoming toxic by inhibiting the CMA-mediated degradation of other cytosolic substrate proteins [51,55] It is not clear whether CMA dysfunction may contribute to the initial formation of insoluble inclusions, it is quite possible that the “blockage effect” on CMA may exacerbate the formation of inclusion bodies by increasing misfolded protein concentrations in the cytoplasm. Despite this common “blockage” mode of action, the CMA dysfunction phenotype of different neurodegenerative diseases may not be completely identical since the expression levels of CMA markers, LAMP2A and Hsc, and CMA activity itself, vary among different diseases.
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