Molecular Mechanisms of Neuronal Death and Strategies for Neuroprotection

我们研究了由CAG-三联体重复疾病引起的遗传性神经疾病中神经元死亡的分子机制，如亨廷顿病和脊髓小脑性共济失调。我们还探讨了帕金森病黑质神经元死亡的分子机制，帕金森病是一种典型的神经退行性疾病，由环境因素和遗传易感性的相互作用引起。此外，我们还研究了保护这些神经元免于退化的策略。在CAG-三联体重复障碍方面，我们成功地产生了亨廷顿病、齿状苍白球-苍白球变性和马查多-约瑟夫病的转基因动物。我们发现突变的萎缩蛋白-3蛋白易位，包括延长的聚谷氨酰胺伸展到细胞核。易位突变蛋白在核内形成包涵体。此外，突变的萎缩蛋白-3与转移因子相互作用并抑制依赖于CREB的转录激活。在帕金森氏病中，…更简单的是，我们确定了一种常染色体隐性遗传型家族性帕金森病的基因，并将其命名为parkin。然后我们对Parkin蛋白的功能进行了分析，发现Parkin蛋白是一种泛素蛋白连接酶。此外，我们确定了Parkin蛋白的候选底物，包括22 kDa的α-突触核蛋白和PAEL(Parkin相互作用的内皮素受体样受体)受体。在Parkin突变患者中也证实了这些蛋白质的积累。因此，这种底物的积累可能是黑质神经退行性变的原因。在散发性帕金森病中，我们确定了可能导致黑质神经变性的候选内源性神经毒素，即N-甲基沙林醇和3‘，4’-二羟基苯并四氢异喹啉。我们发现，Bcl2与SMN相互作用，增强了Bcl2的神经保护作用。此外，我们还发现了一种新的蛋白质DP5，它在细胞凋亡级联被激活时被激活。此外，我们还发现了一种来自肝脏的新的神经营养因子。这种物质显著刺激外周和中枢神经元的再生。因此，我们的团队阐明了许多导致神经元死亡的重要分子途径。为了解神经退行性变的分子机制和神经保护做出了重要贡献。较少

We investigated molecular mechanisms of neuronal death in hereditary neurologic disorders due to CAG-triplet repeat diseases such as Huntington's disease and spinocerebellar ataxias. Also we investigated molecular mechanisms of nigral neuronal death in Parkinson's disease, which is a representative neurodegenerative disorders caused by the interaction of environmental factors and genetic predisposition. In addition, we investigated strategies for protecting these neurons from degeneration.Regarding CAG-triplet repeat disorders, we succeeded in the generation of transgenic animals of Huntington's disease, dentatorubral-pallidoluysian degeneration, and Machado-Joseph disease. We found translocation of mutated atrophin-3 protein including the elongated polyglutamine stretch to the nucleus. Translocated mutant proteins formed intranuclear inclusions. In addition, mutated atrophin-3 interacted with a transfer factor and inhibited CREB-dependent activation of transcription.In Parkinson's dis … More ease, we identified the gene for an autosomal recessive form of familial Parkinson's disease linked to the long arm of chromosome 6 and named it as parkin. Then we analyzed the function of the parkin protein and found that the parkin protein was an ubiquitin-protein ligase. Furthermore, we identified candidate substrates for the parkin protein, including 22 kDa alpha-synuclein and PAEL (Parkin-interacting endothelin receptor like) receptor. Accumulation of these proteins was also confirmed in patients with parkin mutations. Thus accumulation of such substrates may be responsible for neurodegeneration of the substantia nigra. In sporadic Parkinson's disease, we identified candidate endogenous neurotoxins, I.e., N-methylRsalsolinol and 3'4'-dihydroxybenzyl tetrahydroisoquinoline, which may contribute to nigral neurodegeneration.Then we investigated strategies for neuroprotection. We found that Bcl-2 interacted with Smn and augmented neuroprotective properties of Bcl-2. In addition, we found a new protein, DP5, which was activated when the apoptosis cascade was activated. Furthermore, we found a new neurotrophic factor derived from the liver. This substance stimulated significantly the regeneration of the peripheral as well as central neurons.Thus our group elucidated many important molecular pathways, which lead neurons to death. We contributed greatly to the understanding of molecular mechanism of neurodegeneration and neuroprotection. Less