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Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease

Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease
Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease
Huntington's disease (HD), spinocerebellar ataxias types 1 and 3 (SCA1, SCA3), and spinobulbar muscular atrophy (SBMA) are caused by CAG/polyglutamine expansion mutations. A feature of these diseases is ubiquitinated intraneuronal inclusions derived from the mutant proteins, which colocalize with heat shock proteins (HSPs) in SCA1 and SBMA and proteasomal components in SCA1, SCA3, and SBMA. Previous studies suggested that HSPs might protect against inclusion formation, because overexpression of HDJ-2/HSDJ (a human HSP40 homologue) reduced ataxin-1 (SCA1) and androgen receptor (SBMA) aggregate formation in HeLa cells. We investigated these phenomena by transiently transfecting part of huntingtin exon 1 in COS-7, PC12, and SH-SY5Y cells. Inclusion formation was not seen with constructs expressing 23 glutamines but was repeat length and time dependent for mutant constructs with 43–74 repeats. HSP70, HSP40, the 20S proteasome and ubiquitin colocalized with inclusions. Treatment with heat shock and lactacystin, a proteasome inhibitor, increased the proportion of mutant huntingtin exon 1-expressing cells with inclusions. Thus, inclusion formation may be enhanced in polyglutamine diseases, if the pathological process results in proteasome inhibition or a heat-shock response. Overexpression of HDJ-2/HSDJ did not modify inclusion formation in PC12 and SH-SY5Y cells but increased inclusion formation in COS-7 cells. To our knowledge, this is the first report of an HSP increasing aggregation of an abnormally folded protein in mammalian cells and expands the current understanding of the roles of HDJ-2/HSDJ in protein folding.
0022-2593
2898-2903
Wyttenbach, A.
69846a0f-fb60-4a28-84eb-ed865a5e31fa
Carmichael, J.
514345ff-3157-4f8f-8d5f-234728feebe0
Swartz, J.E.
3d22eb95-a7d0-4c35-a561-0b9b4340c581
Furlong, R.A.
68208c6e-6bdb-4de6-bf2a-1e96b84fe55e
Narain, Y.
250fa42a-e4c0-4b7d-8593-4c89236acd73
Rankin, J.
f46fdd1f-6006-4a21-ace2-b4d8d8c85c20
Rubinsztein, D.C.
7bc49386-aa67-4658-a966-0d952e6fd731
Wyttenbach, A.
69846a0f-fb60-4a28-84eb-ed865a5e31fa
Carmichael, J.
514345ff-3157-4f8f-8d5f-234728feebe0
Swartz, J.E.
3d22eb95-a7d0-4c35-a561-0b9b4340c581
Furlong, R.A.
68208c6e-6bdb-4de6-bf2a-1e96b84fe55e
Narain, Y.
250fa42a-e4c0-4b7d-8593-4c89236acd73
Rankin, J.
f46fdd1f-6006-4a21-ace2-b4d8d8c85c20
Rubinsztein, D.C.
7bc49386-aa67-4658-a966-0d952e6fd731

Wyttenbach, A., Carmichael, J., Swartz, J.E., Furlong, R.A., Narain, Y., Rankin, J. and Rubinsztein, D.C. (2000) Effects of heat shock, heat shock protein 40 (HDJ-2), and proteasome inhibition on protein aggregation in cellular models of Huntington's disease. Journal of Medical Genetics, 97 (6), 2898-2903.

Record type: Article

Abstract

Huntington's disease (HD), spinocerebellar ataxias types 1 and 3 (SCA1, SCA3), and spinobulbar muscular atrophy (SBMA) are caused by CAG/polyglutamine expansion mutations. A feature of these diseases is ubiquitinated intraneuronal inclusions derived from the mutant proteins, which colocalize with heat shock proteins (HSPs) in SCA1 and SBMA and proteasomal components in SCA1, SCA3, and SBMA. Previous studies suggested that HSPs might protect against inclusion formation, because overexpression of HDJ-2/HSDJ (a human HSP40 homologue) reduced ataxin-1 (SCA1) and androgen receptor (SBMA) aggregate formation in HeLa cells. We investigated these phenomena by transiently transfecting part of huntingtin exon 1 in COS-7, PC12, and SH-SY5Y cells. Inclusion formation was not seen with constructs expressing 23 glutamines but was repeat length and time dependent for mutant constructs with 43–74 repeats. HSP70, HSP40, the 20S proteasome and ubiquitin colocalized with inclusions. Treatment with heat shock and lactacystin, a proteasome inhibitor, increased the proportion of mutant huntingtin exon 1-expressing cells with inclusions. Thus, inclusion formation may be enhanced in polyglutamine diseases, if the pathological process results in proteasome inhibition or a heat-shock response. Overexpression of HDJ-2/HSDJ did not modify inclusion formation in PC12 and SH-SY5Y cells but increased inclusion formation in COS-7 cells. To our knowledge, this is the first report of an HSP increasing aggregation of an abnormally folded protein in mammalian cells and expands the current understanding of the roles of HDJ-2/HSDJ in protein folding.

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Published date: 1 September 2000

Identifiers

Local EPrints ID: 56797
URI: https://eprints.soton.ac.uk/id/eprint/56797
ISSN: 0022-2593
PURE UUID: 38ddaf93-e113-4380-880f-f8de2aa201b9

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Date deposited: 06 Aug 2008
Last modified: 17 Jul 2017 14:30

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