Oxidation of survival factor MEF2D in neuronal death and Parkinson's disease.
OBJECTIVE
Dysfunction of myocyte enhancer factor 2D (MEF2D), a key survival protein and transcription factor, underlies the pathogenic loss of dopaminergic (DA) neurons in Parkinson's disease (PD). Both genetic factors and neurotoxins associated with PD impair MEF2D function in vitro and in animal models of PD. We investigated whether distinct stress conditions target MEF2D via converging mechanisms.


RESULTS
We showed that exposure of a DA neuronal cell line to 6-hyroxydopamine (6-OHDA), which causes PD in animals models, led to direct oxidative modifications of MEF2D. Oxidized MEF2D bound to heat-shock cognate protein 70 kDa, the key regulator for chaperone-mediated autophagy (CMA), at a higher affinity. Oxidative stress also increased the level of lysosomal-associated membrane protein 2A (LAMP2A), the rate-limiting receptor for CMA substrate flux, and stimulated CMA activity. These changes resulted in accelerated degradation of MEF2D. Importantly, 6-OHDA induced MEF2D oxidation and increased LAMP2A in the substantia nigra pars compacta region of the mouse brain. Consistently, the levels of oxidized MEF2D were much higher in postmortem PD brains compared with the controls. Functionally, reducing the levels of either MEF2D or LAMP2A exacerbated 6-OHDA-induced death of the DA neuronal cell line. Expression of an MEF2D mutant that is resistant to oxidative modification protected cells from 6-OHDA-induced death.


METHODS
This study showed that oxidization of survival protein MEF2D is one of the pathogenic mechanisms involved in oxidative stress-induced DA neuronal death.


CONCLUSIONS
Oxidation of survival factor MEF2D inhibits its function, underlies oxidative stress-induced neurotoxicity, and may be a part of the PD pathogenic process.
1 Department of Neurosurgery, Tangdu Hospital, The Fourth Military Medical University , Xi'an, China .
Li
L
Gao
Hua
H
She
Wenming
W
Li
Jin
J
Zeng
Jinqiu
J
Zhu
Dean P
DP
Jones
Zixu
Z
Mao
Guodong
G
Gao
Qian
Q
Yang
D000818:Animals; D001343:Autophagy; D016923:Cell Death; D002460:Cell Line; D059290:Dopaminergic Neurons / Q000378:metabolism*; D006801:Humans; D064326:MEF2 Transcription Factors / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D016627:Oxidopamine / Q000494:pharmacology*; D010300:Parkinson Disease / Q000378:metabolism*; D065842:Pars Compacta / Q000187:drug effects* / Q000378:metabolism
D064326:MEF2 Transcription Factors; C578043:MEF2D protein, human; C578044:Mef2d protein, mouse; D016627:Oxidopamine