title: Calcium leak through ryanodine receptor is involved in neuronal death induced by mutant huntingtin.
abstract: Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine (polyQ) tract in huntingtin (htt) protein. Although altered calcium (Ca(2+)) homeostasis is suggested in HD, its molecular mechanisms have remained poorly understood despite their important role in the pathogenesis. In this study, we examined involvement of ryanodine receptor (RyR), an endoplasmic reticulum-resident Ca(2+) channel, in mutant htt-induced neuronal death. Inhibitors of RyR attenuated cell death induced by mutant htt, while co-expression of RyR enhanced htt toxicity. Intracellular Ca(2+) imaging revealed that mutant htt caused excessive basal Ca(2+) release (Ca(2+) leak) through RyR leading to depletion of internal Ca(2+) store. Ca(2+) leak was also observed in striatal and cortical neurons from R6/2 HD model mice. Moreover, expression of FK506-binding protein 12 (FKBP12), a RyR stabilizer, suppressed both Ca(2+) leak and cell death. These results provide novel evidence suggesting altered RyR function is involved in neuronal cell death, and its stabilization might be beneficial for treatment of HD.
authors.affiliation: Molecular Neurobiology Laboratory, Division of Life Science, Hokkaido University, Graduate School of Life Science, Sapporo 060-0810, Japan. suzumari@ncnp.go.jp
authors.forename: Mari
authors.initials: M
authors.lastname: Suzuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Nagai
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Koike
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D019837:Ryanodine Receptor Calcium Release Channel; D022061:Tacrolimus Binding Protein 1A; D002118:Calcium