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.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Neural Oxidative Metabolism and Death Study Section (NOMD)
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Wise, Bradley C
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Emory University
Schools of Medicine
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