Neurons, when faced with endogenous and exogenous toxic stress, mobilize their survival machinery. Many human neurological diseases such as Alzheimer's and Parkinson's diseases involve altered neuronal survival and pathological loss of neurons. The long-term objective of this research in our laboratory is to understand at molecular level how neurons respond to stress and the role of dysfunction of survival response in neurodegenerative process. We propose in the current application to study how a neuronal survival protein myocyte enhancer factor 2D (MEF2D), which plays key roles in distinct cellular compartments, is regulated by toxic oxidative signals in neurons and models of neurodegenerative diseases. One of the key common pathways by which diverse toxic signals lead to neurodegenerative process involves oxidative stress and dysfunction of mitochondria. Indeed, several environmental toxicants and genetic alterations associated with AD and PD disrupt mitochondrial activity and induce oxidative stress. Recently, dysfunction of autophagic process has also been shown to play an important role in neuronal stress. However, the key links which propagate the initial oxidative insult in multi subcellular compartments to signal stress and impair survival remain largely unclear. Our previous work showed that nuclear transcription factor MEF2D strongly promotes the survival of several types of neurons. Our recent studies during the last funding cycle revealed that MEF2D is present in mitochondria to directly modulate mitochondrial function and non functional MEF2D is removed by chaperone mediated autophagy (CMA). Disruption of either process sensitizes neurons to stress, leading to death. These novel findings place MEF2D at a key position in multiple subcellular organelles, where it senses and modulates neuronal response to stress. Our preliminary studies suggest that oxidative stress directly modifies MEF2D molecule, impairing its function and regulation in these organelles. Together, these findings support the intriguing hypothesis that MEF2D is a key target of neuronal oxidation and impairment of its function at multi subcellular organelles underlies oxidation-induced stress and contribute to neurodegenerative process. We will combine molecular and cellular methods and animal models to determine in Aim I whether stress causes oxidative modifications of MEF2D in neurons;
in Aim II whether oxidative modifications of MEF2D impair its function and regulation in multiple subcellular organelles in neurons;and in Aim III whether oxidative modifications of MEF2D occur in in vivo models of neurotoxin- induced degeneration and human postmortem brains. This study will identify MEF2D as a key target of oxidative stress in several key organelles and reveal that dysregulation of MEF2D by oxidative modifications may undermine neuronal survival. This novel mechanism may be relevant to the pathogenesis of neurodegenerative diseases and provide basis for developing novel therapeutic strategies for their treatment.

Public Health Relevance

Neurodegenerative disorders including Alzheimer's and Parkinson'diseases are devastating and currently without effective therapy. The specific causes for them are not entirely clear but involve loss of specific populations of neurons. Our study will reveal how a neuronal survival protein is regulated by oxidative stress, a common trigger for neurodegenerative disorders, in multiple key subcellular compartments, and how this may disrupt multiple critical cellular processes. Knowledge gained through this study may help design new therapeutic approaches to treat neurodegenerative diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG023695-07
Application #
8689865
Study Section
Neural Oxidative Metabolism and Death Study Section (NOMD)
Program Officer
Wise, Bradley C
Project Start
2004-09-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Yang, Qian; Li, Wenming; She, Hua et al. (2015) Stress induces p38 MAPK-mediated phosphorylation and inhibition of Drosha-dependent cell survival. Mol Cell 57:721-34
Liu, Xiaolei; Huang, Sihua; Wang, Xingqin et al. (2015) Chaperone-mediated autophagy and neurodegeneration: connections, mechanisms, and therapeutic implications. Neurosci Bull 31:407-15
Gao, Li; She, Hua; Li, Wenming et al. (2014) Oxidation of survival factor MEF2D in neuronal death and Parkinson's disease. Antioxid Redox Signal 20:2936-48
Wei, Gengze; Yin, Yue; Li, Wenming et al. (2012) Calpain-mediated degradation of myocyte enhancer factor 2D contributes to excitotoxicity by activation of extrasynaptic N-methyl-D-aspartate receptors. J Biol Chem 287:5797-805
Yao, Lu; Li, Wenming; She, Hua et al. (2012) Activation of transcription factor MEF2D by bis(3)-cognitin protects dopaminergic neurons and ameliorates Parkinsonian motor defects. J Biol Chem 287:34246-55
She, Hua; Yang, Qian; Mao, Zixu (2012) Neurotoxin-induced selective ubiquitination and regulation of MEF2A isoform in neuronal stress response. J Neurochem 122:1203-10
Wen, Yi; Li, Wenjun; Poteet, Ethan C et al. (2011) Alternative mitochondrial electron transfer as a novel strategy for neuroprotection. J Biol Chem 286:16504-15
She, Hua; Yang, Qian; Shepherd, Kennie et al. (2011) Direct regulation of complex I by mitochondrial MEF2D is disrupted in a mouse model of Parkinson disease and in human patients. J Clin Invest 121:930-40
Li, Wenming; Yang, Qian; Mao, Zixu (2011) Chaperone-mediated autophagy: machinery, regulation and biological consequences. Cell Mol Life Sci 68:749-63
She, Hua; Mao, Zixu (2011) Regulation of myocyte enhancer factor-2 transcription factors by neurotoxins. Neurotoxicology 32:563-6

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