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BAG1 modulates huntingtin toxicity, aggregation, degradation, and subcellular distribution
Author(s) -
Sroka Kamila,
Voigt Aaron,
Deeg Sebastian,
Reed John C.,
Schulz Jörg B.,
Bähr Mathias,
Kermer Pawel
Publication year - 2009
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06363.x
Subject(s) - huntingtin , neuroprotection , microbiology and biotechnology , drosophila melanogaster , toxicity , huntingtin protein , in vivo , transgene , huntington's disease , neurodegeneration , ubiquitin ligase , proteasome , biology , chemistry , ubiquitin , mutant , pharmacology , biochemistry , genetics , medicine , disease , gene , organic chemistry
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 .