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

Molecules

Jan Liman¹  Kamila Sroka¹  Christoph P. Dohm¹  Sebastian Deeg¹  Mathias Bähr¹ 

[1] ¹Deptment of Neurology, University of Göttingen, Robert-Koch Str. 40 37075 Göttingen, Germany

关键词: BAG1;    Huntington’s disease;    Chaperone system;    Siah1;   

DOI  :  10.3390/molecules15106678

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
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.