Effect of trehalose on the properties of mutant {gamma}PKC, which causes spinocerebellar ataxia type 14, in neuronal cell lines and cultured Purkinje cells

J Biol Chem. 2010 Oct 22;285(43):33252-33264. doi: 10.1074/jbc.M110.146704. Epub 2010 Aug 12.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Cell Line
  • Dendrites / enzymology*
  • Dendrites / pathology
  • Enzyme Stability / drug effects
  • Enzyme Stability / genetics
  • Mice
  • Mutation, Missense
  • Protein Kinase C / genetics
  • Protein Kinase C / metabolism*
  • Protein Multimerization / drug effects*
  • Protein Multimerization / genetics
  • Protein Transport / drug effects
  • Protein Transport / genetics
  • Purkinje Cells / enzymology*
  • Purkinje Cells / pathology
  • Spinocerebellar Ataxias / drug therapy
  • Spinocerebellar Ataxias / enzymology*
  • Spinocerebellar Ataxias / genetics
  • Spinocerebellar Ataxias / pathology
  • Trehalose / pharmacology*

Substances

  • Trehalose
  • Protein Kinase C