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Accumulation of ubi...
Accumulation of ubiquitin conjugates in a polyglutamine disease model occurs without global ubiquitin/proteasome system impairment
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- Maynard, Christa J. (författare)
- Karolinska Institutet
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Bottcher, Claudia (författare)
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Ortega, Zaira (författare)
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- Smith, Ruben (författare)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Florea, Bogdan I. (författare)
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Diaz-Hernandez, Miguel (författare)
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- Brundin, Patrik (författare)
- Lund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Department of Experimental Medical Science,Faculty of Medicine
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Overkleeft, Hermen S. (författare)
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- Li, Jia-Yi (författare)
- Lund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups
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Lucas, Jose J. (författare)
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- Dantuma, Nico P. (författare)
- Karolinska Institutet
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(creator_code:org_t)
- 2009-08-18
- 2009
- Engelska.
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 106:33, s. 13986-13991
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Nyckelord
- protein degradation
- Huntington
- neurodegeneration
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- art (ämneskategori)
- ref (ämneskategori)
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Maynard, Christa ...
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Bottcher, Claudi ...
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Ortega, Zaira
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Smith, Ruben
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Florea, Bogdan I ...
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Diaz-Hernandez, ...
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visa fler...
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Brundin, Patrik
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Overkleeft, Herm ...
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Li, Jia-Yi
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Lucas, Jose J.
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Dantuma, Nico P.
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinska och f ...
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och Neurovetenskaper
- Artiklar i publikationen
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Proceedings of t ...
- Av lärosätet
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Lunds universitet
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Karolinska Institutet