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Funded Studies

The Therapeutic Role of CMA-MEF2D in the Survival of DA Neurons

Parkinson’s Disease is caused by the death of a particular group of dopaminergic (DA) neurons in the brain. Our recent studies revealed that a nuclear protein named MEF2D is dysregulated in DA neurons by toxic signals related to the development of Parkinson’s disease. Furthermore, loss of MEF2D function appears to underlie the process of toxic genetic signal-induced death of these key neurons. These findings suggest that increasing the activities of MEF2D in the nerve cells may protect them from toxin-induced death.

Project Description:
We propose to test whether increasing MEF2D can protect neurons from toxic stress in models of PD. We will need to first generate a series of special reagents that can increase the levels and activities of MEF2D when introduced into cells. We will test their effects in cultured DA neurons. Specifically, we will culture DA neurons by isolating them directly from rodent mid brain, expose them to stressful signals, and then determine whether providing DA neurons with MEF2D may protect them from toxicity. If these results are encouraging, we will then proceed to perform in vivo studies using genetically engineered mice. We intend to test whether increasing MEF2D in the brain of rodents can protect neurons from toxicity induced by alpha-synuclein.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Current therapies do not alter the progressive nature of Parkinson’s disease. Since the pathological basis of Parkinson’s disease is the loss of DA neurons, reducing the death of DA neurons holds promise in slowing the progression of the disease. The key for protecting DA neurons lies in identifying the critical targets. Our project is aimed at validating MEF2D as such a target and therefore holds the potential of developing new therapeutic strategy for Parkinson’s disease.

Anticipated Outcome:
Results from this study will tell us whether changing the levels of MEF2D in the nucleus of DA neurons may affect their viability under toxic and stressful conditions. We anticipate that increase of MEF2D should protect DA neurons against toxicity induced by genetic alteration such as alpha-synuclein mutation in cultured neurons and in rodent model of Parkinson’s disease. This would indicate that increasing MEF2D in DA neurons should be explored as a novel treatment for Parkinson’s disease.

Progress Report

Our previous studies have shown that transcription factor myocyte enhancer factor 2 (MEF2) promotes the survival of different populations of neurons under various experimental paradigms.  Our recent work showed that dysregulation of MEF2D by chaperone-mediated autophagy may underlie alpha-synuclein-induced neurotoxicity in models of PD.  We investigated the possibility of targeting MEF2D as therapeutic strategy to protect dopaminergic neurons.  Our data indicated that MEF2D is required for the survival of primary DA neurons under basal condition.  Increase in MEF2D activity protects a dopaminergic neuronal cell line, SN47371, from alpha-synuclein toxicity and protects primary DA neurons from MPP+ toxicity.  These findings are consistent with the possibility that MEF2D may serve as a therapeutic target.


  • Zixu Mao, PhD

    Atlanta, GA United States

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