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Science 323 (5910): 124-127

Copyright © 2009 by the American Association for the Advancement of Science

Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediated Autophagy

Qian Yang,1 Hua She,1 Marla Gearing,2 Emanuela Colla,3 Michael Lee,3 John J. Shacka,4 Zixu Mao1,2*

Abstract: 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.

1 Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
2 Department of Neurology, Emory University School of Medicine, Atlanta, GA 30322, USA.
3 Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4 Department of Pathology, Division of Neuropathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.

* To whom correspondence should be addressed. E-mail: zmao{at}pharm.emory.edu

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