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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 α-synuclein transgenic mice and patients with Parkinson's disease. Wild-type α-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.In neurodegenerative diseases, certain populations of adult neurons are gradually lost because of toxic stress. The four myocyte enhancer factor 2 (MEF2) transcription factors, MEF2A to MEF2D, have been shown to play an important role in the survival of several types of neurons, and a genetic polymorphism of the MEF2A gene has been linked to the risk of late onset of Alzheimer's disease (1-3). In cellular models, inhibition of MEF2s contributes to neuronal death. Enhancing MEF2 activity protects neurons from death in vitro and in the substantia nigra pars compacta in a mouse model of Parkinson's disease (PD) (4). Neurotoxic insults cause MEF2 degradation in part by a caspase-dependent mechanism (5), but how MEF2 is regulated under basal conditions without overt toxicity is unknown. Autophagy refers to the degradation of intracellular components by lysosomes. Relative to macro-and microautophagy, chaperonemediated autophagy (CMA) selectively degrades cytosolic proteins (6). This process involves binding of heat shock protein Hsc70 to substrate proteins via a KFERQ-like motif and their subsequent targeting to lysosomes via the lysosomal membrane receptor Lamp2a. Dysregulation of autophagy plays a role in neurodegeneration (7-9). However, the direct mechanism by which CMA modulates neuronal survival or death is unclear.