Huntington's disease (HD) is one of several major neurodegenerative diseases caused by expanded polyglutamine (polyQ) repeats (usually >36 glutamines) in the huntingtin protein (mutant huntingtin, mtHtt). The presence of the abnormal expansion of polyQ in this protein often causes alteration in normal cellular functions and leads detrimental effects, but still its exact role in the initiation and progression of HD is far less known, and no drugs are available to slow down or prevent the progression of HD. Mitochondrial dysfunction has been identified as a potential cause of HD, because neuronal survival and function are highly dependent on mitochondria functionality. Particularly, dysregulation of removal of damaged mitochondria, a process referred to as mitophagy, contributes to the progression and/or development of HD by impairing the elimination of defective mitochondria and thus causing neuronal damage. Given impaired mitophagy as a potential cause of HD, insight into the molecular basis of this process may suggest a new means to prevent or slow down the pathology associated with HD. Towards this end, we characterized a potential molecular mechanism involved in the process of impaired mitophagy in a cell culture model of HD. We first identified a novel molecular mechanism by which glyceraldehyde-3-phosphate dehydrogenase (GAPDH) associates with damaged mitochondria and triggers mitophagy in cells under oxidative stress conditions. However, mtHtt with expanded polyglutamine (Q74) inhibited this process by interacting with GAPDH and thus leading to accumulation of damaged mitochondria around lysosome. In order to disrupt the interaction between GAPDH and mtHtt and thus rescue GAPDH-induced mitophagy, we are currently designing a peptide targeting this interaction. Together, all studies elucidate the role of GAPDH and mtHtt interaction in clearance of damaged mitochondria through mitophagy, and will be the first step in evaluating the potential utility of inhibiting this protein-protein interaction to interrupt the pathology in HD.

Elucidation of the interaction between mutant huntingtin protein (mtHtt) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) for mitochondrial elimination in Huntington's disease (HD)

248th National Meeting (2014)

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