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Molecules 2010, 15(10), 6678-6687; doi:10.3390/molecules15106678

Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain

1,2, 1,2
1 Deptment of Neurology, University of Göttingen, Robert-Koch Str. 40 37075 Göttingen, Germany 2 DFG-Research Center for Molecular Physiology of the Brain (CMPB), Humboldtallee 23, 37075 Göttingen, Germany 3 Merz Pharmaceuticals, R&D CNS, In vitro Pharmacology, Eckenheimer Landstrasse 100, 60318 Frankfurt, Germany These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 11 August 2010 / Revised: 16 September 2010 / Accepted: 19 September 2010 / Published: 28 September 2010
(This article belongs to the Special Issue Neuroprotective Strategies)
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Huntington´s disease, one of the so-called poly-glutamine diseases, is a dominantly inherited movement disorder characterized by formation of cytosolic and nuclear inclusion bodies and progressive neurodegeneration. Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo of the disease-specific mutant huntingtin protein. Aiming at future small molecule-based therapeutical approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGDC. We show that disruption of the BAG domain known to eliminate intracellular heat shock protein 70 (Hsp70) binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGDC fails to induce increased proteasomal huntingtin turnover and does not inhibit intracellular huntingtin aggregation, a pre-requisite necessary for prevention of huntingtin toxicity.
Keywords: BAG1; Huntington’s disease; Chaperone system; Siah1 BAG1; Huntington’s disease; Chaperone system; Siah1
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Liman, J.; Sroka, K.; Dohm, C.P.; Deeg, S.; Bähr, M.; Kermer, P. Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain. Molecules 2010, 15, 6678-6687.

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