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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 3.0).

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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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