Mechanism of neuroprotection by the heat shock proteins in amyotrophic lateral sclerosis model mice (SOD1-G93S transgenic mice)

1.建立ALS转基因小鼠神经系统蛋白质组图谱（Gurney et al.）。Science 1994)我们绘制了青年和老年ALS Tg小鼠神经系统的蛋白质组图谱（可溶部分和不可溶部分）。我们已经给药了几种可能的神经保护药物，并分析了蛋白质组学变化和生命周期，到目前为止，我们还没有发现HSP诱导剂对ALS Tg小鼠的显著治疗作用3。利用培养细胞寻找SOD1结合蛋白我们利用Neuro2A细胞系免疫沉淀法寻找可能的SOD1结合蛋白候选物。两个HSPs， HSc70和HSP105，被发现是SOD1结合蛋白。我们的发现发表在《神经化学杂志》上。基于我们假设的可能的治疗方法我们发现HSP105抑制培养细胞中含有聚集体的突变SOD1的形成。这一结果表明，提高HSP105水平的技术可能是减轻突变SOD1毒性的有希望的工具。

1.Establishing proteome map of nervous system of ALS transgenic mice (Gurney et al. Science 1994)We have made proteome map (soluble fraction and insoluble fraction) of nervous system of young and old ALS Tg mice.2.Analysis of therapeutic effect and proteome change by administering neuroprotective HSP inducers to the ALS transgenic miceWe have administrated several possible neuroprotective drugs and analyzed proteomic change and life period, so far we could not document significant therapeutic effect of HSP inducers on ALS Tg mice3.Searching for SOD1 binding proteins using culture cellsWe searched for possible SOD1 binding protein candidates by immunoprecipitation using Neuro2A cell line. Two HSPs, HSc70 and HSP105, are found to be SOD1 binding proteins. Our finding was published on Journal of Neurochemistry.4.Possible therapeutic method based on our hypothesisWe found that HSP105 suppresses the formation of mutant SOD1 containing aggregates in cultured cell. This result suggests that techniques that raise levels of HSP105 might be promising tools for alleviation of the mutant SOD1 toxicity.