Chaperone mediated autophagy to the rescue: A new-fangled target for the treatment of neurodegenerative diseases.

One of the main pathways of lysosomal proteolysis is chaperone-mediated autophagy (CMA), which represents a selective mechanism for the degradation of specific soluble proteins within lysosomes. Along with the other two lysosomal pathways, macro- and micro-autophagy, CMA contributes to cellular quality control through the removal of damaged or malfunctioning proteins. The two intrinsic characteristics of CMA are the selective targeting and the direct translocation of substrate proteins into the lysosomal lumen, in a fine-tuned manner through the orchestrated action of a chaperone/co-chaperone complex localized both at the cytosol and the lysosomes. Even though CMA was originally identified as a stress-induced pathway, basal CMA activity is detectable in most cell types analyzed so far, including neurons. Additionally, CMA activity declines with age and this may become a major aggravating factor contributing to neurodegeneration. More specifically, it has been suggested that CMA impairment may underlie the accumulation of misfolded/aggregated proteins, such as alpha-synuclein or LRRK2, whose levels or conformations are critical to Parkinson's disease pathogenesis. On the other hand, CMA induction might accelerate clearance of pathogenic proteins and promote cell survival, suggesting that CMA represents a viable therapeutic target for the treatment of various proteinopathies. In the current review, we provide an overview of the current state of knowledge regarding the role of CMA under physiological and pathological conditions of the nervous system and discuss the implications of these findings for therapeutic interventions for Parkinson's disease and other neurodegenerative disorders. This article is part of Special Issue entitled "Neuronal Protein".

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