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Chaperone mediated autophagy 20198/26/2023 Notably, rats with reduced CMA in the brain quickly exhibit loss of dopaminergic neurons in the substantia nigra and display Parkinson’s-like motor symptoms ( Xilouri et al., 2016). The findings of this study represent an important first step in repurposing class I PI3K inhibitors to modulate CMA in vivo.ĬMA plays a role in preventing disease pathogenesis by degrading proteins with causative roles in hepatosteatosis, neoplasia, and a number of neurodegenerative diseases ( Gomes et al., 2017 Schneider et al., 2014 Kaushik and Cuervo, 2018). Isolated liver lysosomes from mice treated with either of two orally bioavailable class I PI3K inhibitors, pictilisib or buparlisib, display elevated CMA activity, and decreased phosphorylation of lysosomal GFAP, with no change in macroautophagy. In contrast, selective inhibition of class III PI3Ks does not activate CMA. Here, we report that inhibition of class I PI3K or PDPK1 activates CMA. The INS-PI3K-PDPK1 pathway regulates Akt, but its role in CMA is unclear. At the lysosomal membrane, CMA is inhibited by Akt-dependent phosphorylation of the CMA regulator GFAP. ![]() CMA regulates the abundance of many disease-related proteins, with causative roles in neoplasia, neurodegeneration, hepatosteatosis, and other pathologies relevant to human health and aging. Chaperone-mediated autophagy (CMA) is the most selective form of lysosomal proteolysis, where individual peptides, recognized by a consensus motif, are translocated directly across the lysosomal membrane.
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