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Brain. 2015 Oct;138(Pt 10):3030-47. doi: 10.1093/brain/awv188. Epub 2015 Jun 30.

Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington's disease.

Author information

1
1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
2
2 Department of Molecular and Life Sciences, Hanyang University, Ansan, 425-791, South Korea.
3
3 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
4
4 VA Boston Healthcare System, Department of Neurology and Boston University Alzheimer's Disease Centre, Boston University School of Medicine, Boston, MA 02118, USA.
5
5 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University College of Medicine or Pharmacy, Seoul, 110-799, South Korea.
6
6 Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, 305-764, South Korea.
7
4 VA Boston Healthcare System, Department of Neurology and Boston University Alzheimer's Disease Centre, Boston University School of Medicine, Boston, MA 02118, USA 7 Centre for Neuromedicine, Brain Science Institute, Korea Institute of Science and Technology, Seoul, 136-791, South Korea hoonryu@bu.edu insuk@snu.ac.kr.
8
1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea hoonryu@bu.edu insuk@snu.ac.kr.

Erratum in

Abstract

Aberrant glutathione or Ca(2+) homeostasis due to oxidative stress is associated with the pathogenesis of neurodegenerative disorders. The Ca(2+)-permeable transient receptor potential cation (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 Cys176/Cys178 residues. The oxidized glutathione-activated TRPC5-like current results in a sustained increase in cytosolic Ca(2+), activated calmodulin-dependent 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 Ca(2+)-permeable channel, and stimulated Ca(2+)-dependent apoptosis in Huntington's disease cells (STHdh(Q111/111)). 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.

KEYWORDS:

Ca2+; GSSG; TRPC; cysteine; neurodegeneration

PMID:
26133660
PMCID:
PMC4643628
DOI:
10.1093/brain/awv188
[Indexed for MEDLINE]
Free PMC Article

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