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.2.神经保护性HSP诱导剂对ALS转基因小鼠的治疗效果和蛋白质组变化的分析我们已经使用了几种可能的神经保护药物，并分析了蛋白质组的变化和生命周期，到目前为止，我们还没有发现HSP诱导剂对ALS TG小鼠有显著的治疗作用。3.利用培养细胞寻找SOD1结合蛋白。两个热休克蛋白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。4.基于我们的假设的可能的治疗方法我们发现HSP105可以抑制培养细胞中含有突变的SOD1聚集体的形成。这一结果表明，提高HSP105水平的技术可能是缓解突变SOD1毒性的有前途的工具。

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.