ポリグルタミン病の異常蛋白構造に基づく病態と治療へのアプローチ Pathomechanism of polyglutamine diseases and strategic design for their therapies

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著者

    • 貫名 信行 NUKINA Nobuyuki
    • 理化学研究所脳科学総合研究センター構造神経病理研究チーム Laboratory for Structural Neuropathology, RIKEN Brain Science Institute

抄録

The pathomechanism of neurodegenerative disorders are not fully elucidated yet. In Huntington Disease (HD) and some hereditary spinocerebellar ataxias, expanded polyglutamine (polyQ) accumulates and forms aggregates in neuronal nuclei. We have been studying the pathological process by which the mutation induces the misfolding and accumulation of the gene product leading to neuronal degeneration using cell biological and structural biological approaches. We analyzed the pathological process in polyQ disease cellular model and the structural changes of polyQ-induced protein misfolding using our polyQ-bearing myoglobin model system. Using these models, we found that expanded polyQ forms a beta-sheet structure and causes proteasome inhibition. We further analyzed the structural basis of toxic aggregates, which suggested the polyglutamine exposed form may be more toxic to sequester several important functional molecules. We also established the method for analyzing aggregate interacting proteins (AIPs) and reported several AIPs including transcription factor NF-Y.<br> Based on the pathomechanism, which we revealed, we developed several experimental therapies, including stabilizing abnormal protein, activating proteasomal function and enhancing the selective degradation of abnormal protein through chaperone-mediated autophagy.<br>

収録刊行物

  • 臨床神経学

    臨床神経学 48(11), 913-914, 2008-11-01

    Societas Neurologica Japonica

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