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

作者：Sroka Kamila; Voigt Aaron; Deeg Sebastian; Reed John C; Schulz Jorg B; Baehr Mathias; Kermer Pawel^*

来源：Journal of Neurochemistry, 2009, 111(3): 801-807.

DOI：10.1111/j.1471-4159.2009.06363.x

• aggregation
• Bcl-2-associated athanogene-1
• Huntington's disease
• proteasomal degradation
• polyglutamine
• seven in absentia homolog 1

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.

• 出版日期2009-11
• 单位河北医科大学