Regulation of neuronal survival factor MEF2D by chaperone-mediated autophagy (Science, 2009, 323:124-127)

報告日期: 2009/05/08
報告時間: 16:00/16:50
報告學生: 劉威廷
講評老師: 莊季瑛
附件下載:

http://basicmed.med.ncku.edu.tw/admin/up_img/980508-2.pdf

Regulation of Neuronal Survival Factor MEF2D by Chaperone-Mediate Autophagy

 

Qian Yang, Hua She, Marla Gearing, Emanuela Colla, Michael Lee,

John J. Shacka, Zixu Mao

Science 323, 124-127, 2009

 

Speaker: Wei-Ting Liu (劉威廷)

Commentator: Jih-Ing Chuang, Ph.D. (莊季瑛 老師)

Time: 16:00-16:50, May 8, 2009

Place: room 602

 

Abstract

    Myocyte enhancer factor 2 (MEF2) family comprising 4 members (MEF2A, -B, -C and –D) are nuclear transcription factors involved in neuronal survival, differentiation, and synaptic function. Several studies support a prosurvival role for this group of proteins by demonstrating that their inhibition contributes to neuronal death, whereas enhancing their activity is protective against toxic cellular stress. However, it was unknown how the MEF2D isoform was regulated under basal conditions. Chaperone-mediated autophagy (CMA) is a process which selectively regulates the levels of specific cytoplasmic proteins. Although autophagy in general widely involved in various cellular processes including aging and neurodegeneration, it is unclear what role of CMA plays in cellular survival and death. The authors provided in vitro and in vivo data from knockout mice, transgenic mice and human brains to show that chaperone-mediated autophagy directly targets MEF2 for lysosomal degradation. MEF2D was observed to continuously shuttle to the cytoplasm, interact with the chaperone Hsc70, and undergo degradation. Inhibition of CMA by pharmacological and genetic strategies caused accumulation of inactive MEF2D in the cytoplasm. Furthermore, cytoplasmic MEF2D levels were increased in the brains of Parkinson’s disease-associated a-synuclein mutant mice and patients with Parkinson’s disease. Overexpressed wild-type or mutant a-synuclein in vitro disrupted the MEF2D-Hsc70 binding and led to neuronal death. Thus, CMA can directly modulate the neuronal survival machinery and disruption of this process by mutant and/or overexpressed a-synuclein leads to accumulation of non-functional MEF2D which may underlie the pathogenic process of Parkinson’s disease.

 

References

1.     Mao, Z., et al. Neuronal Activity-Dependent Cell Survival Mediated by Transcription Factor MEF2. Science 286, 785–790, 1999.

2.     Dice, J.F. Chaperone-Mediated Autophagy. Autophagy 3, 295–299, 2007.

3.     Cuervo, A.M., et al. Impaired Degradation of Mutant a-Synuclein by Chaperone-Mediated Autophagy. Science 305, 1292–1295, 2004.