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Heat shock promotes inclusion body formation of mutant huntingtin (mHtt) and alleviates mHtt-induced transcription factor dysfunction.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2018 Oct 05; Vol. 293 (40), pp. 15581-15593. Date of Electronic Publication: 2018 Aug 24. - Publication Year :
- 2018
-
Abstract
- PolyQ-expanded huntingtin (mHtt) variants form aggregates, termed inclusion bodies (IBs), in individuals with and models of Huntington's disease (HD). The role of IB versus diffusible mHtt in neurotoxicity remains unclear. Using a ponasterone (PA)-inducible cell model of HD, here we evaluated the effects of heat shock on the appearance and functional outcome of Htt103Q <superscript>Exon1</superscript> -EGFP expression. Quantitative image analysis indicated that 80-90% of this mHtt protein initially appears as "diffuse" signals in the cytosol, with IBs forming at high mHtt expression. A 2-h heat shock during the PA induction reduced the diffuse signal, but greatly increased mHtt IB formation in both cytosol and nucleus. Dose- and time-dependent mHtt expression suggested that nucleated polymerization drives IB formation. RNA-mediated knockdown of heat shock protein 70 (HSP70) and heat shock cognate 70 protein (HSC70) provided evidence for their involvement in promoting diffuse mHtt to form IBs. Reporter gene assays assessing the impacts of diffuse versus IB mHtt showed concordance of diffuse mHtt expression with the repression of heat shock factor 1, cAMP-responsive element-binding protein (CREB), and NF-κB activity. CREB repression was reversed by heat shock coinciding with mHtt IB formation. In an embryonic striatal neuron-derived HD model, the chemical chaperone sorbitol similarly promoted the structuring of diffuse mHtt into IBs and supported cell survival under stress. Our results provide evidence that mHtt IB formation is a chaperone-supported cellular coping mechanism that depletes diffusible mHtt conformers, alleviates transcription factor dysfunction, and promotes neuron survival.<br /> (© 2018 Chen et al.)
- Subjects :
- Animals
Cell Nucleus drug effects
Cell Nucleus metabolism
Cell Nucleus pathology
Corpus Striatum metabolism
Corpus Striatum pathology
Cyclic AMP Response Element-Binding Protein genetics
Cyclic AMP Response Element-Binding Protein metabolism
Cytosol drug effects
Cytosol metabolism
Cytosol pathology
Ecdysterone analogs & derivatives
Ecdysterone pharmacology
Embryo, Mammalian
Gene Expression Regulation
HSC70 Heat-Shock Proteins genetics
HSC70 Heat-Shock Proteins metabolism
HSP70 Heat-Shock Proteins genetics
HSP70 Heat-Shock Proteins metabolism
Heat Shock Transcription Factors metabolism
Huntingtin Protein metabolism
Huntington Disease chemically induced
Huntington Disease metabolism
Huntington Disease pathology
Inclusion Bodies chemistry
Inclusion Bodies drug effects
Models, Biological
Mutation
NF-kappa B genetics
NF-kappa B metabolism
Neurons drug effects
Neurons pathology
PC12 Cells
Primary Cell Culture
Rats
Sorbitol pharmacology
Heat Shock Transcription Factors genetics
Heat-Shock Response
Huntingtin Protein genetics
Huntington Disease genetics
Inclusion Bodies metabolism
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 293
- Issue :
- 40
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 30143534
- Full Text :
- https://doi.org/10.1074/jbc.RA118.002933