BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution

2009 | journal article; research paper. A publication with affiliation to the University of Göttingen.

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​Sroka, Kamila, Aaron Voigt, Sebastian Deeg, John C. Reed, Jörg B. Schulz, Mathias Bähr, and Pawel Kermer. "BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution​." ​Journal of Neurochemistry ​111, no. 3 (2009): ​801​-807​. ​https://doi.org/10.1111/j.1471-4159.2009.06363.x.

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Authors
Sroka, Kamila ; Voigt, Aaron ; Deeg, Sebastian ; Reed, John C.; Schulz, Jörg B. ; Bähr, Mathias ; Kermer, Pawel 
Abstract
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.
Issue Date
2009
Journal
Journal of Neurochemistry 
ISSN
0022-3042
eISSN
1471-4159
Language
English

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