THE ROLE OF GAP JUNCTIONS IN OXIDATIVE NEURODEGENERATION IN CEREBELLUM

这个子项目是众多研究子项目之一

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The passage of apoptotic signals through gap junctions has been implicated in oxidative cell death and neurodegenerative disorders. Gap junction proteins play important roles in cerebellum. Protein kinase C gamma (PKCgamma) is a neuronal specific PKC. Activated PKCgamma phosphorylates and inhibits gap junctions, a process which is controlled by a cell oxidative state. C1B1 peptides activate PKCgamma by competitively binding to its docking protein 14-3-3. Mutations in PKCgamma cause spinocerebellar ataxia type 14 (SCA-14), an autosomal, dominant neurodegenerative disorder in humans with onset ages of three to thirty years. Thus, mutations of PKCgamma would cause a failure of the cell or animal to respond to oxidative stress by inhibition of gap junctions, which subsequently results in oxidative cell death. In this proposal we will determine how gap junctions are controlled by PKCgamma activation and what the effect of inhibition of gap junctions on neural apoptosis. We will also characterize the defects in cerebellar response to oxidative stress in the PKCgamma H101Y SCA14 transgenic mouse models. We have demonstrated that exposure of PKCgamma knockout mice to hyperbaric oxygen results in severe loss of Purkinje cells, an effect not observed in control mice. Overexpression of the PKCgamma H101Y SCA14 mutation leads to significant loss of Purkinje cells in transgenic mice. The improper control of gap junctions in PKCgamma knockout and/or transgenic mice may account for Purkinje neuron degeneration. This information will provide direction for the design of drugs to delay or prevent oxidative neurodegeneration by restoration of control of gap junctions.