Abstract: 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
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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.
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.
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.