Journal
JOURNAL OF NEUROCHEMISTRY
Volume 111, Issue 3, Pages 801-807Publisher
WILEY
DOI: 10.1111/j.1471-4159.2009.06363.x
Keywords
aggregation; Bcl-2-associated athanogene-1; Huntington's disease; proteasomal degradation; polyglutamine; seven in absentia homolog 1
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Funding
- CMPB
- High Q foundation
- European Commission [MEST-CT-2004-504193]
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Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein delivering chaperone-recognized unfolded substrates to the proteasome for degradation. It has been shown to be essential for proper CNS development in vivo, playing a crucial role in neuronal survival and differentiation. With regard to Huntington's disease, a sequestration of BAG1 into inclusion bodies and a neuroprotective effect in double transgenic mice have been reported. Here, we show that BAG1 reduces aggregation and accelerates degradation of mutant huntingtin (htt-mut). Moreover, it reduces nuclear levels of htt-mut. This effect can be overcome by over-expression of seven in absentia homolog 1, an E3 ligase negatively regulated by BAG1 and known to be involved in nuclear import of htt-mut. In vivo, BAG1 proved to be protective in a Drosophila melanogaster Huntington's disease model, preventing photoreceptor cell loss induced by htt-mut. In summary, we present BAG1 as a therapeutic tool modulating key steps in htt toxicity in vitro and ameliorating htt toxicity in vivo.
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