Decreased protein synthesis of Hsp27 associated with cellular toxicity in a cell model of Machado-Joseph disease.

Abstract	Machado-Joseph disease is an autosomal dominant spinocerebellar degeneration caused by the expansion of a polyglutamine tract within the gene product, ataxin-3. We have previously shown that increased oxidative stress and decreased expression of Hsp27 may be contributory factors to the disease progression. In this study, we utilized neuroblastoma SK-N-SH cells stably transfected with full-length expanded ataxin-3 to further investigate the mechanism(s) resulting in the decreased expression of Hsp27. Results from 35S-methionine pulse-chase labeling and protein degradation assays revealed that decreased Hsp27 in mutant MJD cells is due to defects in protein synthesis. Our results further demonstrated that Hsp27 degradation is independent of the proteasome degradation pathway. In addition, we showed that overexpression of Hsp27 desensitizes mutant MJD cells to apoptotic stress. Taken together, these findings provide the first evidence that expanded ataxin-3 interferes with Hsp27 synthesis, which may contribute to the impairment of the cells' ability to respond to stresses and trigger the progression of this late-onset disease.
Authors	Wei-Hsiu Chang, Chih-Liang Tien, Tzu-Jung Chen, Nobuyuki Nukina, Mingli Hsieh
Journal	Neuroscience letters (Neurosci Lett) Vol. 454 Issue 2 Pg. 152-6 (Apr 24 2009) ISSN: 0304-3940 [Print] Ireland
PMID	19429074 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	Cysteine Proteinase Inhibitors HSP27 Heat-Shock Proteins HSPB1 protein, human Heat-Shock Proteins Leupeptins Molecular Chaperones Nerve Tissue Proteins Nuclear Proteins Peptides RNA, Messenger Repressor Proteins acetylleucyl-leucyl-norleucinal polyglutamine ATXN3 protein, human Ataxin-3 benzyloxycarbonylleucyl-leucyl-leucine aldehyde
Topics	Animals Ataxin-3 Blotting, Western COS Cells Cell Line, Tumor Chlorocebus aethiops Cysteine Proteinase Inhibitors (pharmacology) Gene Expression HSP27 Heat-Shock Proteins (biosynthesis) Heat-Shock Proteins Humans Leupeptins (pharmacology) Machado-Joseph Disease (metabolism) Molecular Chaperones Nerve Tissue Proteins (genetics, metabolism) Neurons (drug effects, metabolism) Nuclear Proteins (genetics, metabolism) Peptides RNA, Messenger (metabolism) Repressor Proteins (genetics, metabolism) Reverse Transcriptase Polymerase Chain Reaction Stress, Physiological Transfection

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