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Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain
AbstractHuntington´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.
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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.View more citation formats
Liman J, Sroka K, Dohm CP, Deeg S, Bähr M, Kermer P. Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain. Molecules. 2010; 15(10):6678-6687.Chicago/Turabian Style
Liman, Jan; Sroka, Kamila; Dohm, Christoph P.; Deeg, Sebastian; Bähr, Mathias; Kermer, Pawel. 2010. "Modulation of Huntingtin Toxicity by BAG1 is Dependent on an Intact BAG Domain." Molecules 15, no. 10: 6678-6687.