title: Mutant γPKC that causes spinocerebellar ataxia type 14 upregulates Hsp70, which protects cells from the mutant's cytotoxicity.
abstract: Several missense mutations in the protein kinase Cγ (γPKC) gene have been found to cause spinocerebellar ataxia type 14 (SCA14), an autosomal dominant neurodegenerative disease. We previously demonstrated that the mutant γPKC found in SCA14 is misfolded, susceptible to aggregation and cytotoxic. Molecular chaperones assist the refolding and degradation of misfolded proteins and prevention of the proteins' aggregation. In the present study, we found that the expression of mutant γPKC-GFP increased the levels of heat-shock protein 70 (Hsp70) in SH-SY5Y cells. To elucidate the role of this elevation, we investigated the effect of siRNA-mediated knockdown of Hsp70 on the aggregation and cytotoxicity of mutant γPKC. Knockdown of Hsp70 exacerbated the aggregation and cytotoxicity of mutant γPKC-GFP by inhibiting this mutant's degradation. These findings suggest that mutant γPKC increases the level of Hsp70, which protects cells from the mutant's cytotoxicity by enhancing its degradation.
authors.affiliation: Department of Molecular and Pharmacological Neuroscience, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ogawa
authors.forename: Takahiro
authors.initials: T
authors.lastname: Seki
authors.forename: Tomoya
authors.initials: T
authors.lastname: Onji
authors.forename: Naoko
authors.initials: N
authors.lastname: Adachi
authors.forename: Shigeru
authors.initials: S
authors.lastname: Tanaka
authors.forename: Izumi
authors.initials: I
authors.lastname: Hide
authors.forename: Naoaki
authors.initials: N
authors.lastname: Saito
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D051379:Mice; D020125:Mutation, Missense; D011493:Protein Kinase C / Q000235:genetics* / Q000378:metabolism; D059748:Proteolysis; D020754:Spinocerebellar Ataxias; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D018840:HSP70 Heat-Shock Proteins; D007770:L-Lactate Dehydrogenase; C087857:protein kinase C gamma; D011493:Protein Kinase C
keywords: 17-AAG; 17-allylamino-17-demethoxygeldanamycin; Aggregation; CHIP; Cytotoxicity; GFP; Heat-shock protein 70; Hsc70; Hsp40; Hsp70; Hsp90; JNK; LDH; PCs; Purkinje cells; SCA14; Spinocerebellar ataxia; WT; c-Jun N-terminal kinase; carboxyl terminus of Hsp70-interacting protein; green fluorescent protein; heat-shock cognate protein 70; heat-shock protein 40; heat-shock protein 70; heat-shock protein 90; lactate dehydrogenase; protein kinase Cγ; spinocerebellar ataxia type 14; wild-type; γPKC