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Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1α

Hyrskyluoto, Alise; Bruelle, Céline; Hult Lundh, Sofia LU ; Do, Hai Thi; Kivinen, Jenny; Rappou, Elisabeth; Reijonen, Sami; Waltimo, Tuure; Petersén, Åsa LU and Lindholm, Dan, et al. (2014) In Human Molecular Genetics 23(22). p.5928-5939
Abstract
Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system.... (More)
Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity. (Less)
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Contribution to journal
publication status
published
subject
in
Human Molecular Genetics
volume
23
issue
22
pages
5928 - 5939
publisher
Oxford University Press
external identifiers
  • pmid:24951540
  • wos:000344671900007
  • scopus:84911440935
ISSN
0964-6906
DOI
10.1093/hmg/ddu317
language
English
LU publication?
yes
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a25ab32d-550d-4c20-99ab-f6e0b410feca (old id 4527397)
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http://www.ncbi.nlm.nih.gov/pubmed/24951540?dopt=Abstract
date added to LUP
2014-07-06 20:08:11
date last changed
2017-10-22 03:24:33
@article{a25ab32d-550d-4c20-99ab-f6e0b410feca,
  abstract     = {Huntington's disease (HD) is an autosomal inherited neurological disease caused by a CAG-repeat expansion in the first exon of huntingtin gene encoding for the huntingtin protein (Htt). In HD, there is an accumulation of intracellular aggregates of mutant Htt that negatively influence cellular functions. The aggregates contain ubiquitin, and part of the HD pathophysiology could result from an imbalance in cellular ubiquitin levels. Deubiquitinating enzymes are important for replenishing the ubiquitin pool, but less is known about their roles in brain diseases. We show here that overexpression of the ubiquitin-specific protease-14 (Usp14) reduces cellular aggregates in mutant Htt-expressing cells mainly via the ubiquitin proteasome system. We also observed that the serine-threonine kinase IRE1 involved in endoplasmic reticulum (ER) stress responses is activated in mutant Htt-expressing cells in culture as well as in the striatum of mutant Htt transgenic (BACHD) mice. Usp14 interacted with IRE1 in control cells but less in mutant Htt-expressing cells. Overexpression of Usp14 in turn was able to inhibit phosphorylation of IRE1α in mutant Htt-overexpressing cells and to protect against cell degeneration and caspase-3 activation. These results show that ER stress-mediated IRE1 activation is part of mutant Htt toxicity and that this is counteracted by Usp14 expression. Usp14 effectively reduced cellular aggregates and counteracted cell degeneration indicating an important role of this protein in mutant Htt-induced cell toxicity.},
  author       = {Hyrskyluoto, Alise and Bruelle, Céline and Hult Lundh, Sofia and Do, Hai Thi and Kivinen, Jenny and Rappou, Elisabeth and Reijonen, Sami and Waltimo, Tuure and Petersén, Åsa and Lindholm, Dan and Korhonen, Laura},
  issn         = {0964-6906},
  language     = {eng},
  number       = {22},
  pages        = {5928--5939},
  publisher    = {Oxford University Press},
  series       = {Human Molecular Genetics},
  title        = {Ubiquitin-specific protease-14 reduces cellular aggregates and protects against mutant huntingtin-induced cell degeneration: involvement of the proteasome and ER stress-activated kinase IRE1α},
  url          = {http://dx.doi.org/10.1093/hmg/ddu317},
  volume       = {23},
  year         = {2014},
}