| Summary: | 碩士 === 中山醫學大學 === 醫學研究所 === 92 === Machado-Joseph disease (MJD)/Spinocerebellar Ataxia Type 3 (SCA3) is an autosomal dominant spinocerebellar degeneration characterized by a wide range of clinical manifestations. The molecular mechanisms underlying the selective neuronal death typical of MJD/SCA3 are unknown. In this study, human SK-N-SH neuroblastoma cells stably transfected with full-length MJD with 78 CAG repeats were assayed for the dynamic expression of Hsp27, known as a suppressor of poly (Q) mediated cell death, in the presence of mutant ataxin-3 during disease progression. Even though a dramatic decrease of Hsp27 expression was observed in the earlier generation of SK-N-SH-MJD78 cells, the aged generation showed a significant increase of Hsp27 to almost the same level of that of the parental cells. Furthermore, immunohistochemical analysis of MJD transgenic mice brain and post-mortem human brain tissues showed increased expression of Hsp27 compared to normal control brain, suggesting an up-regulation of Hsp27 in end stage of MJD. While heat shock was used to assess the stress response, cells expressing mutant ataxin-3 displayed normal response upon heat shock stimuli when compared to the parental cells. However, cells expressing mutant ataxin-3 showed weak tolerance upon serum depletion and oxidative stress. Our results demonstrated that the protein expression of Hsp27 is greatly influenced by the accumulation and long-term chronic exposure of expanded full-length ataxin-3. We proposed that during the early disease stage, the reduction of Hsp27 synthesis mitigated the ability of cells to cope with cytotoxicity induced by cellular stresses. In the late stage of disease, after prolonged stressful conditions of polyglutamine cytotoxicity, even though the increased concentration of polyglutamine or the appearance of nuclear inclusions of polyglutamine eventually stimulate HSP response, this increased HSP response still cannot reverse the global dysfunction of cellular proteins due to accumulation of cytotoxic effects.
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