Protective effect of neuronal chaperone-mediated autophagy against brain aging and disease-driven neuroproteotoxicity

Components of the proteostasis network malfunction in the aging brain and this reduced neuronal protein quality control has been proposed to increase risk for neurodegeneration. Here, we have focused on chaperone-mediated autophagy (CMA), a selective type of autophagy that contributes to turnover of neurodegeneration-related proteins. We generated mouse models with CMA blockage in dopaminergic or glutamatergic neurons to investigate the physiological role of CMA in neurons in vivo and the consequences of neuronal CMA loss in aging, We found that loss of neuronal CMA leads to behavioral impairments, altered neuronal function, selective changes in the neuronal proteome and proteotoxicity, all reminiscent of brain aging. Furthermore, imposing CMA loss on an experimental mouse model of Alzheimer’s disease, increased neuronal disease vulnerability and accelerated disease progression. We conclude that functional CMA is essential for neuronal proteostasis and that CMA activation could be an efficient disease-modifying therapy in neurodegenerative disorders.