Studies on molecular mechanisms of polyglutamine diseases and its treatment with molecular

（1）热休克蛋白（Heat shock proteins，Hsp）参与多种疾病的病理生理过程，如癌症、糖尿病和神经退行性疾病，影响Hsp水平的小分子物质有望用于治疗多种疾病。我们已经证明，水杨酸钠（SA）激活热休克启动子，诱导热休克蛋白的表达。在这项研究中，我们研究了所需的功能基团的SA诱导热休克反应，并揭示，苯羟基，而不是羧基的SA似乎是必要的诱导热休克反应。在这些化合物中，水杨醇，强烈诱导Hsp70的表达抑制蛋白质聚集和细胞凋亡所造成的扩大多聚谷氨酰胺道在多聚谷氨酰胺疾病的细胞模型。因此，SA的一些衍生物可用于保护细胞免受有害的应激源和神经退行性疾病。（2）Hsp 105是一种分子伴侣，在从酵母到人类的生物体中高度保守，在哺乳动物的多种组织中表达，但在脑中表达量较高。我们已经证明，Hsp105的过表达抑制了由多聚谷氨酰胺的扩增引起的细胞凋亡，并且Hsp105在脑中的表达可能为CAG重复疾病提供有效的治疗手段。在这项研究中，我们研究了由热休克蛋白105的聚谷氨酰胺的扩展引起的细胞凋亡的抑制机制，并揭示了热休克蛋白105抑制细胞凋亡通过抑制蛋白质的核聚集和热休克蛋白105的核定位是必要的抑制细胞凋亡。这些发现可能有助于开发治疗多聚谷氨酰胺疾病的新型有效药物。

(1)Heat shock proteins (Hsp) are involved in the pathophysiology of several diseases such as cancer, diabetes and neurodegenerative disorders, the small molecules that influence the level of Hsp are expected to be useful for the treatment of various diseases. We have shown that sodium salicylate (SA) activates the heat shock promoter and induces the expression of Hsp. In this study, we examined the functional groups of SA necessary for the induction of Hsp, and revealed that the phenylic hydroxyl group but not carboxyl group of SA seemed to be necessary for the induction of heat shock response. Among these compounds, salicylalcohol that strongly induced the expression of Hsp70 suppressed the protein aggregation and apoptosis caused by an expanded polyglutamine tract in a cellular model of polyglutamine disease. Therefore, some derivatives of SA may be used for the protection of cells against deleterious stressors and neurodegenerative diseases.(2)Hsp 105 is a molecular chaperone which is highly conserved in organisms from yeast to human and is expressed in various tissues of mammals, but especially at high levels in brain. We have shown that over-expression of Hsp105 suppresses apoptosis caused by an expansion of polyglutamine and expression of Hsp 105 in brain may provide an effective therapeutic means for CAG repeat diseases. In this study, we examined the inhibition mechanisms of apoptosis caused by an expansion of polyglutamine by Hsp 105 and revealed that Hsp 105 inhibited the apoptosis by suppressing the nuclear aggregation of the protein and the nuclear localization of Hsp 105 was necessary for the inhibition of apoptosis. These findings may aid in the development of novel effective drug for the treatment of polyglutamine diseases.