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

(1)热休克蛋白（Hsp）参与癌症、糖尿病、神经退行性疾病等多种疾病的病理生理，影响热休克蛋白水平的小分子有望用于多种疾病的治疗。我们发现水杨酸钠（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，我们检测了SA诱导热休克反应所必需的官能团，发现SA的苯基羟基而不是羧基似乎是诱导热休克反应所必需的。在这些化合物中，水杨醇强烈诱导Hsp70的表达，抑制了聚谷氨酰胺疾病细胞模型中由扩大的聚谷氨酰胺束引起的蛋白质聚集和细胞凋亡。因此，一些SA衍生物可用于保护细胞免受有害应激源和神经退行性疾病的侵害。(2)热休克蛋白105是一种在酵母和人类等生物中高度保守的分子伴侣，在哺乳动物的各种组织中均有表达，尤其是在大脑中表达水平较高。我们的研究表明，过表达Hsp105可抑制聚谷氨酰胺扩增引起的细胞凋亡，在脑内表达Hsp105可能为CAG重复疾病提供有效的治疗手段。在本研究中，我们研究了Hsp 105对聚谷氨酰胺扩增引起的细胞凋亡的抑制机制，发现Hsp 105通过抑制蛋白的核聚集来抑制细胞凋亡，并且Hsp 105的核定位是抑制细胞凋亡的必要条件。这些发现可能有助于开发治疗多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.