title: Effect of trehalose on the properties of mutant {gamma}PKC, which causes spinocerebellar ataxia type 14, in neuronal cell lines and cultured Purkinje cells.
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 susceptible to aggregation, which induces apoptotic cell death. The disaccharide trehalose has been reported to inhibit aggregate formation and to alleviate symptoms in cellular and animal models of Huntington disease, Alzheimer disease, and prion disease. Here, we show that trehalose can be incorporated into SH-SY5Y cells and reduces the aggregation of mutant γPKC-GFP, thereby inhibiting apoptotic cell death in SH-SY5Y cells and primary cultured Purkinje cells (PCs). Trehalose acts by directly stabilizing the conformation of mutant γPKC without affecting protein turnover. Trehalose was also found to alleviate the improper development of dendrites in PCs expressing mutant γPKC-GFP without aggregates but not in PCs with aggregates. In PCs without aggregates, trehalose improves the mobility and translocation of mutant γPKC-GFP, probably by inhibiting oligomerization and thereby alleviating the improper development of dendrites. These results suggest that trehalose counteracts various cellular dysfunctions that are triggered by mutant γPKC in both neuronal cell lines and primary cultured PCs by inhibiting oligomerization and aggregation of mutant γPKC.
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551.
authors: Takahiro
authors: T
authors: Seki
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551.
authors: Nana
authors: N
authors: Abe-Seki
authors: National Institute of Agrobiological Sciences, Ohwashi 1-2, Tsukuba, Ibaraki 305-8634.
authors: Takahiro
authors: T
authors: Kikawada
authors: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors: Hideyuki
authors: H
authors: Takahashi
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551.
authors: Kazuhiro
authors: K
authors: Yamamoto
authors: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors: Naoko
authors: N
authors: Adachi
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551.
authors: Shigeru
authors: S
authors: Tanaka
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551.
authors: Izumi
authors: I
authors: Hide
authors: Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan.
authors: Naoaki
authors: N
authors: Saito
authors: From the Department of Molecular and Pharmacological Neuroscience, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima 734-8551. Electronic address: nsakai@hiroshima-u.ac.jp.
authors: Norio
authors: N
authors: Sakai
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D003712:Dendrites / Q000201:enzymology* / Q000473:pathology; D004795:Enzyme Stability / Q000187:drug effects / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization / Q000187:drug effects* / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D011689:Purkinje Cells / Q000201:enzymology* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014199:Trehalose / Q000494:pharmacology*
chemical_list: D014199:Trehalose; D011493:Protein Kinase C