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

Maynard, Christa J.; Bottcher, Claudia; Ortega, Zaira; Smith, Ruben LU ; Florea, Bogdan I.; Diaz-Hernandez, Miguel; Brundin, Patrik LU ; Overkleeft, Hermen S.; Li, Jia-Yi LU and Lucas, Jose J., et al. (2009) In Proceedings of the National Academy of Sciences 106(33). p.13986-13991
Abstract
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... (More)
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. (Less)
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publication status
published
subject
keywords
protein degradation, Huntington, neurodegeneration
in
Proceedings of the National Academy of Sciences
volume
106
issue
33
pages
13986 - 13991
publisher
National Acad Sciences
external identifiers
  • wos:000269078700066
  • scopus:69549131138
ISSN
1091-6490
DOI
10.1073/pnas.0906463106
language
English
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yes
id
752553b2-c44c-42d4-9de7-adab2423de99 (old id 1476885)
date added to LUP
2009-09-28 11:33:37
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2017-11-12 03:21:23
@article{752553b2-c44c-42d4-9de7-adab2423de99,
  abstract     = {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.},
  author       = {Maynard, Christa J. and Bottcher, Claudia and Ortega, Zaira and Smith, Ruben and Florea, Bogdan I. and Diaz-Hernandez, Miguel and Brundin, Patrik and Overkleeft, Hermen S. and Li, Jia-Yi and Lucas, Jose J. and Dantuma, Nico P.},
  issn         = {1091-6490},
  keyword      = {protein degradation,Huntington,neurodegeneration},
  language     = {eng},
  number       = {33},
  pages        = {13986--13991},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences},
  title        = {Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment},
  url          = {http://dx.doi.org/10.1073/pnas.0906463106},
  volume       = {106},
  year         = {2009},
}