title: Deficit of heat shock transcription factor 1-heat shock 70 kDa protein 1A axis determines the cell death vulnerability in a model of spinocerebellar ataxia type 6.
abstract: Spinocerebellar ataxia type 6 (SCA6) is caused by a small expansion of polyglutamine (polyQ)-encoding CAG repeat in Ca(v)2.1 calcium channel gene. To gain insights into pathogenic mechanism of SCA6, we used HEK293 cells expressing fusion protein of enhanced green fluorescent protein and Ca(v)2.1 carboxyl terminal fragment (EGFP-Ca(v)2.1CT) [L24 and S13 cells containing 24 polyQ (disease range) and 13 polyQ (normal range), respectively] and examined their responses to some stressors. When exposed to CdCl(2), L24 cells showed lower viability than the control S13 cells and caspase-dependent apoptosis was enhanced more in L24 cells. Localization of EGFP-Ca(v)2.1CT was almost confined to the nucleus, where it existed as speckle-like structures. Interestingly, CdCl(2) treatment resulted in disruption of more promyelocytic leukemia nuclear bodies (PML-NBs) in L24 cells than in S13 cells and in cells where PML-NBs were disrupted, aggregates of EGFP-Ca(v)2.1CT became larger. Furthermore, a large number of aggregates were formed in L24 cells than in S13 cells. Results of RNAi experiments indicated that HSPA1A determined the difference against CdCl(2) toxicity. Furthermore, protein expression of heat shock transcription factor 1 (HSF1), which activates HSPA1A expression, was down-regulated in L24 cells. Therefore, HSF1-HSPA1A axis is critical for the vulnerability in L24 cells.
authors.affiliation: Department of Pharmacology and Neurobiology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Hironao
authors.initials: H
authors.lastname: Saegusa
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Tanabe
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D019256:Cadmium Chloride / Q000633:toxicity; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D015536:Down-Regulation; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics* / Q000378:metabolism*; D000076249:Heat Shock Transcription Factors; D006358:Hot Temperature; D006801:Humans; D007150:Immunohistochemistry; D046228:Microarray Analysis; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020754:Spinocerebellar Ataxias / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*
chemical_list: D020746:Calcium Channels, L-Type; D004268:DNA-Binding Proteins; C000619706:HSF1 protein, human; D018840:HSP70 Heat-Shock Proteins; C490786:HSPA1A protein, human; D000076249:Heat Shock Transcription Factors; C419385:L-type calcium channel alpha(1C); D014157:Transcription Factors; D019256:Cadmium Chloride