Chansik Hong
Chosun University, South Korea
Title: Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington’s disease
Biography
Biography: Chansik Hong
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 Huntington’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 Huntington’s disease transgenic (YAC128)
mice. Increased levels of endogenous TRPC5 S-glutathionylation were observed in the striatum in both transgenic mice and
patients with Huntington’s disease. Both knockdown and inhibition of TRPC5 significantly attenuated oxidation-induced
striatal neuronal cell death. Moreover, a TRPC5 blocker improved rearing behaviour in Huntington’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 Huntington’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 Huntington’s disease.