学术报告

报告题目:Control of Gap Junctions in Neurodegeneration

报 告 人:Dr. Dingbo Lin, Assistant Professor, Human Nutrition, Kansas State University

报告时间: 2009年1月7日上午10:00点

报告地点: 生物II馆#122

邀 请 人: 陶涛教授

Control of Gap Junctions in Neurodegeneration

Dingbo Lin

Assistant Professor

Human Nutrition, Kansas State University

The long-term goal of my research is to understand control of gap junctions inprotection of cells from oxidative stress damage and to develop potential treatments for neurodegeneration. I am particularly interested in cellsignalling in stress-induced retinal degeneration and cerebellar neurodegeneration in vitro and in vivo. Currently I am working on two projects supported by NIH. The retinal degeneration project is focused on cell apoptotic signalling in retinal pigment epithelial cells and neuroprotection from diabetic retinal degeneration by dietary supplements using type 2 diabetic animal models. The cerebellar degeneration project is focused on molecular mechanism of cerebellar neurodegeneration using a novel PKCg spinocerebellar ataxia type 14 (SCA14) transgenic mouse model which was published recently. We have determined that PKCg mutations in the C1B domain lack PKCγ stress sensing activity. The cells with these mutants are more susceptible to protein aggregation, which, in turn, results in caspase-3-linked apoptosis in neuronal HT22 cells. The cell apoptotic signals are spreaded to adjacent cells through non-controlled, open gap junctions. To test if impaired cellular stress responses and cerebellar cell death occur in vivo, I have generated the first PKCg H101Y transgenic mice in the world. This is a novel model for SCA14. Degeneration of cerebellar Purkinje cells occurs in these transgenic mice at 4 weeks of age. The PKCγ H101Y mutation expressed in the transgenic mouse has a dominant negative effect on endogenous PKCγ enzyme activity. Absence of PKCγ activity in vivo results in a total loss of brain connexin 57 phosphorylation on serines, which may result in caspase-12 and -3 activation, neuronal cell death, and motor function disturbances in the PKCγ H101Y SCA14 transgenic mouse in vivo. Novel gap junction inhibitors, C1B1 peptides and PQ1, protect Purkinje cells from apoptosis through restoration of PKCγ control of gap junctions in slice cultures of the transgenic mice and in HT22 cells in vitro.