Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediated Autophagy

Chaperone- mediated autophagy controls the degradation of selective cytosolic proteins and may protect neurons against degeneration. In a neuronal cell line, we found that chaperone- mediated autophagy regulated the activity of myocyte enhancer factor 2D ( MEF2D), a transcription factor required for neuronal survival. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of chaperone- mediated autophagy caused accumulation of inactive MEF2D in the cytoplasm. MEF2D levels were increased in the brains of alpha-synuclein transgenic mice and patients with Parkinson's disease. Wild-type alpha-synuclein and a Parkinson's disease- associated mutant disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, chaperone- mediated autophagy modulates the neuronal survival machinery, and dysregulation of this pathway is associated with Parkinson's disease.