Dynamic expression of Hsp27 in the presence of mutant ataxin-3.
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 in different passages of cultured cells. A dramatic decrease of Hsp27 expression was observed in the earlier passage of cultured SK-N-SH-MJD78 cells, however, the later passage of cells showed a significant increase of Hsp27 to almost the same level of the parental cells. Furthermore, immunohistochemical analysis of MJD transgenic mice and post-mortem human brain tissues showed increased expression of Hsp27 compared to normal control brain, suggesting an up-regulation of Hsp27 in the end stage of MJD. However, mutant cells of earlier passages were more susceptible to serum deprivation than mutant cells of later passages, indicating weak tolerance toward stress in cells with reduced Hsp27. 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. Taken together, we proposed that during the early disease stage, the reduction of Hsp27 synthesis mitigated the ability of neuron cells to cope with cytotoxicity induced by mutant ataxin-3, triggering the cell death process during the disease progress. In the late stage of disease, after prolonged stressful conditions of polyglutamine cytotoxicity, the increased level of Hsp27 may reflect a dynamic process of the survived cells to unfold and remove mutant ataxin-3. However, this increased Hsp27 still cannot reverse the global dysfunction of cellular proteins due to accumulation of cytotoxic effects.
Chang
Wei-Hsiu
WH
Department of Life Science, Tunghai University, Taichung, Taiwan.
Cemal
Cemal K
CK
Hsu
Yung-Hsiang
YH
Kuo
Cheng-Liang
CL
Nukina
Nobuyuki
N
Chang
Ming-Hong
MH
Hu
Hsiao-Tang
HT
Li
Chuan
C
Hsieh
Mingli
M
D000818:Animals; D000067699:Ataxin-3; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D016895:Culture Media, Serum-Free; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017827:Machado-Joseph Disease / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins; D011180:Postmortem Changes; D012097:Repressor Proteins; D014157:Transcription Factors
D016895:Culture Media, Serum-Free; D006360:Heat-Shock Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors; C092341:ATXN3 protein, human; D000067699:Ataxin-3; C511594:Atxn3 protein, mouse