title: Cell and Context-Dependent Effects of the Heat Shock Protein DNAJB6 on Neuronal Survival.
abstract: Previous studies performed in cell lines have shown that the heat shock protein, DNAJB6, protects against the proteotoxic effects of mutant huntingtin (mut-Htt) via direct interaction with mut-Htt. However, these studies were performed primarily using in vitro models and cell lines. We report that when expressed in primary neurons, DNAJB6 induces cell death. Neurotoxicity is observed with both the DNAJB6a isoform, which is strictly nuclear, and the DNAJB6b isoform, which is predominantly cytoplasmic, suggesting that neurotoxicity is mediated in the nucleus. However, when co-expressed in primary neurons with mut-Htt, DNAJB6 protects against mut-Htt neurotoxicity. This suggests that the contrasting effect of DNAJB6 on neuronal viability depends on the presence or absence of proteotoxic stress. Neurotoxicity of DNAJB6 cannot be prevented by inhibition of glycogen synthase kinase 3 beta (GSK3β) or c-Jun N-terminal kinase (JNK) but is prevented by pharmacological inhibition of cyclin-dependent kinases (CDKs). Expression of dominant-negative forms of CDK2 or CDK4, or of p21(CIP1), the physiological inhibitor of CDKs, also inhibits DNAJB6 neurotoxicity. DNAJB6 neurotoxicity can also be inhibited by histone deacetylase-4 (HDAC4), which interacts with DNAJB6 and which has previously been described to inhibit cell cycle progression. These results conclude that neurotoxicity resulting from elevated DNAJB6 is cell cycle dependent.
authors.affiliation: Department of Biological Sciences, Southern Methodist University, Dedman Life Sciences Building, 6501 Airline Road, Dallas, TX, 75275, USA.|Department of Molecular and Cell Biology, University of Texas at Dallas, Richardson, TX, 75080, USA.
authors.forename: Chad
authors.initials: C
authors.lastname: Smith
authors.affiliation: Department of Biological Sciences, Southern Methodist University, Dedman Life Sciences Building, 6501 Airline Road, Dallas, TX, 75275, USA. sdmello@smu.edu.
authors.forename: Santosh R
authors.initials: SR
authors.lastname: D'Mello
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D057809:HEK293 Cells; D050956:HSP40 Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D000071058:Huntingtin Protein / Q000633:toxicity; D051379:Mice; D008938:Mitosis / Q000187:drug effects; D050505:Mutant Proteins / Q000633:toxicity; D041681:NIH 3T3 Cells; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009498:Neurotoxins / Q000633:toxicity; D011485:Protein Binding / Q000187:drug effects; D034741:RNA, Small Interfering / Q000378:metabolism; D017208:Rats, Wistar; D013312:Stress, Physiological / Q000187:drug effects
chemical_list: C000625966:Dnajb6 protein, rat; D050956:HSP40 Heat-Shock Proteins; D000071058:Huntingtin Protein; D050505:Mutant Proteins; D009498:Neurotoxins; D034741:RNA, Small Interfering; D018844:Cyclin-Dependent Kinases
keywords: DNAJB6; Heat shock proteins; Huntington’s disease; Neurodegeneration; Neuronal death; Neuronal survival