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Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment

In English

Författare

  • Christa J. Maynard
  • Claudia Bottcher
  • Zaira Ortega
  • Ruben Smith
  • Bogdan I. Florea
  • Miguel Diaz-Hernandez
  • Patrik Brundin
  • Hermen S. Overkleeft
  • Jia-Yi Li
  • Jose J. Lucas
  • Nico P. Dantuma
Visa allt

Summary, in English

Aggregation-prone proteins have been suggested to overwhelm and impair the ubiquitin/proteasome system (UPS) in polyglutamine (polyQ) disorders, such as Huntington's disease (HD). Overexpression of an N-terminal fragment of mutant huntingtin (N-mutHtt), an aggregation-prone polyQ protein responsible for HD, obstructs the UPS in cellular models. Furthermore, based on the accumulation of polyubiquitin conjugates in brains of R6/2 mice, which express human N-mutHtt and are one of the most severe polyQ disorder models, it has been proposed that UPS dysfunction is a consistent feature of this pathology, occurring in both in vitro and in vivo models. Here, we have exploited transgenic mice that ubiquitously express a ubiquitin fusion degradation proteasome substrate to directly assess the functionality of the UPS in R6/2 mice or the slower onset R6/1 mice. Although expression of N-mutHtt caused a general inhibition of the UPS in PC12 cells, we did not observe an increase in the levels of proteasome reporter substrate in the brains of R6/2 and R6/1 mice. We show that the increase in ubiquitin conjugates in R6/2 mice can be primarily attributed to an accumulation of large ubiquitin conjugates that are different from the conjugates observed upon UPS inhibition. Together our data show that polyubiquitylated proteins accumulate in R6/2 brain despite a largely operative UPS, and suggest that neurons are able to avoid or compensate for the inhibitory effects of N-mutHtt.

Publiceringsår

2009

Språk

Engelska

Sidor

13986-13991

Publikation/Tidskrift/Serie

Proceedings of the National Academy of Sciences

Volym

106

Issue

33

Dokumenttyp

Artikel i tidskrift

Förlag

National Academy of Sciences

Ämne

  • Neurosciences

Nyckelord

  • protein degradation
  • Huntington
  • neurodegeneration

Status

Published

Forskningsgrupp

  • Neural Plasticity and Repair

ISBN/ISSN/Övrigt

  • ISSN: 1091-6490