title: Increased TRPC5 glutathionylation contributes to striatal neuron loss in Huntington's disease.
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.
authors.affiliation: 1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Chansik
authors.initials: C
authors.lastname: Hong
authors.affiliation: 2 Department of Molecular and Life Sciences, Hanyang University, Ansan, 425-791, South Korea.
authors.forename: Hyemyung
authors.initials: H
authors.lastname: Seo
authors.affiliation: 1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Misun
authors.initials: M
authors.lastname: Kwak
authors.affiliation: 2 Department of Molecular and Life Sciences, Hanyang University, Ansan, 425-791, South Korea.
authors.forename: Jeha
authors.initials: J
authors.lastname: Jeon
authors.affiliation: 2 Department of Molecular and Life Sciences, Hanyang University, Ansan, 425-791, South Korea.
authors.forename: Jihoon
authors.initials: J
authors.lastname: Jang
authors.affiliation: 3 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Eui Man
authors.initials: EM
authors.lastname: Jeong
authors.affiliation: 1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Jongyun
authors.initials: J
authors.lastname: Myeong
authors.affiliation: 4 VA Boston Healthcare System, Department of Neurology and Boston University Alzheimer's Disease Centre, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Yu Jin
authors.initials: YJ
authors.lastname: Hwang
authors.affiliation: 1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Kotdaji
authors.initials: K
authors.lastname: Ha
authors.affiliation: 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.
authors.forename: Min Jueng
authors.initials: MJ
authors.lastname: Kang
authors.affiliation: 6 Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, 305-764, South Korea.
authors.forename: Kyu Pil
authors.initials: KP
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Eugene C
authors.initials: EC
authors.lastname: Yi
authors.affiliation: 3 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: In-Gyu
authors.initials: IG
authors.lastname: Kim
authors.affiliation: 1 Department of Physiology and Institute of Dermatological Science, Seoul National University College of Medicine, Seoul, 110-799, South Korea.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: 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.
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.affiliation: 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.
authors.forename: Insuk
authors.initials: I
authors.lastname: So
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology*; D005978:Glutathione / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D050052:TRPC Cation Channels / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D050052:TRPC Cation Channels; C491780:TRPC5 protein, human; D049452:Green Fluorescent Proteins; D005978:Glutathione; D002118:Calcium
keywords: Ca2+; GSSG; TRPC; cysteine; neurodegeneration