Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntingtons disease

Joint Event on 4^th International Conference on Epilepsy & Treatment & 4^th World Congress on Parkinsons & Huntington Disease

August 29-30, 2018 | Zurich, Switzerland

Chansik Hong

Chosun University, South Korea

Posters & Accepted Abstracts: J Neurol Disord

Abstract :

Aberrant glutathione or Ca2+ homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca2+-permeable TRPC channel is predominantly expressed in the brain which is sensitive to oxidative stress. However, the role of the TRPC channel in neurodegeneration is not known. Here, we report a mechanism of TRPC5 activation by oxidants and the effect of glutathionylated TRPC5 on striatal neurons in Huntingtonâ??s disease. Intracellular oxidized glutathione leads to TRPC5 activation via TRPC5 S-glutathionylation at cysteine-176/cysteine-178 residues. The oxidized glutathione-activated TRPC5-like current, results in a sustained increase in cytosolic Ca2+, activated calmodulindependent protein kinase and the calpain-caspase pathway, ultimately inducing striatal neuronal cell death. We observed an abnormal glutathione pool indicative of an oxidized state in the striatum of Huntingtonâ??s disease transgenic (YAC128) mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and patients with Huntingtonâ??s disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntingtonâ??s disease transgenic mice and motor behavioural symptoms in littermate control mice by increasing striatal neuron survival. Notably, low levels of TRPC1 increased the formation of TRPC5 homotetramer, a highly Ca2+-permeable channel, and stimulated Ca2+-dependent apoptosis in Huntingtonâ??s disease cells (STHdhQ111/111). Taken together, these novel findings indicate that increased TRPC5 S-glutathionylation by oxidative stress and decreased TRPC1 expression contribute to neuronal damage in the striatum and may underlie neurodegeneration in Huntingtonâ??s disease.

Biography :

Chansik Hong completed his PhD from Seoul National University and Post-doctorate from Seoul National University, College of Medicine. He is an Associate Professor in the Physiology Department at Chosun University, College of Medicine. He has published more than 25 papers on ion channels in reputed journals.

E-mail: cshong@chosun.ac.kr