Chaperone-mediated autophagy as a sex-specific modulator of synaptic proteostasis and neural function

in adult mice, the authors revealed sexually divergent synaptic phenotypes: females exhibit enhanced presynaptic neurotransmitter release and GRIN/NMDAR-mediated plasticity, while males show increased postsynaptic GRIA/AMPAR activity due to impaired receptor endocytosis. These changes are driven by sex-specific degradation of synaptic proteins such as SYN1 (synapsin I) in females and AP2A/α-Adaptin in males. Importantly, reactivation of CMA - either genetically or pharmacologically - rescues synaptic dysfunction, seizure susceptibility, and memory deficits in aged mice and Alzheimer disease models. This commentary contextualizes these findings within the broader framework of activity-dependent proteostasis, sex-specific autophagy modulation, and therapeutic potential of CMA in brain aging and neurodegeneration.