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.
Yang
Qian
Q
Department of Pharmacology, Emory University School of Medicine, Atlanta, GA 30322, USA.
She
Hua
H
Gearing
Marla
M
Colla
Emanuela
E
Lee
Michael
M
Shacka
John J
JJ
Mao
Zixu
Z
D020816:Amino Acid Motifs; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D003593:Cytoplasm / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D026161:MADS Domain Proteins / Q000378:metabolism*; D064326:MEF2 Transcription Factors; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000378:metabolism*; D018006:Myogenic Regulatory Factors / Q000737:chemistry / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism; D011485:Protein Binding; D021381:Protein Transport; D051381:Rats; D020318:Rats, Long-Evans; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism
D050883:HSC70 Heat-Shock Proteins; C494372:Hspa8 protein, mouse; D052119:Lysosomal-Associated Membrane Protein 2; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; C578044:Mef2d protein, mouse; D018832:Molecular Chaperones; D018006:Myogenic Regulatory Factors; D051844:alpha-Synuclein; D000643:Ammonium Chloride; D004247:DNA