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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

In English

Författare

  • Alise Hyrskyluoto
  • Céline Bruelle
  • Sofia Hult Lundh
  • Hai Thi Do
  • Jenny Kivinen
  • Elisabeth Rappou
  • Sami Reijonen
  • Tuure Waltimo
  • Åsa Petersén
  • Dan Lindholm
  • Laura Korhonen
Visa allt

Summary, in English

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.

Publiceringsår

2014

Språk

Engelska

Sidor

5928-5939

Publikation/Tidskrift/Serie

Human Molecular Genetics

Volym

23

Issue

22

Dokumenttyp

Artikel i tidskrift

Förlag

Oxford University Press

Ämne

  • Medical Genetics

Status

Published

Forskningsgrupp

  • Translational Neuroendocrinology

ISBN/ISSN/Övrigt

  • ISSN: 0964-6906