Leyva Melissa J, Degiacomo Francesco, Kaltenbach Linda S, Holcomb Jennifer, Zhang Ningzhe, Gafni Juliette, Park Hyunsun, Lo Donald C, Salvesen Guy S, Ellerby Lisa M, Ellman Jonathan A
Department of Chemistry, University of California, Berkeley, CA 94720, USA.
Chem Biol. 2010 Nov 24;17(11):1189-200. doi: 10.1016/j.chembiol.2010.08.014.
Huntington's Disease (HD) is characterized by a mutation in the huntingtin (Htt) gene encoding an expansion of glutamine repeats on the N terminus of the Htt protein. Numerous studies have identified Htt proteolysis as a critical pathological event in HD postmortem human tissue and mouse HD models, and proteases known as caspases have emerged as attractive HD therapeutic targets. We report the use of the substrate activity screening method against caspase-3 and -6 to identify three novel, pan-caspase inhibitors that block proteolysis of Htt at caspase-3 and -6 cleavage sites. In HD models these irreversible inhibitors suppressed Hdh(111Q/111Q)-mediated toxicity and rescued rat striatal and cortical neurons from cell death. In this study, the identified nonpeptidic caspase inhibitors were used to confirm the role of caspase-mediated Htt proteolysis in HD. These results further implicate caspases as promising targets for HD therapeutic development.
亨廷顿舞蹈症（HD）的特征是亨廷顿蛋白（Htt）基因发生突变，该突变导致Htt蛋白N端的谷氨酰胺重复序列扩增。大量研究已确定Htt蛋白水解是HD患者死后组织和小鼠HD模型中的关键病理事件，而被称为半胱天冬酶的蛋白酶已成为有吸引力的HD治疗靶点。我们报告了使用针对半胱天冬酶-3和-6的底物活性筛选方法，以鉴定三种新型的泛半胱天冬酶抑制剂，这些抑制剂可阻断Htt在半胱天冬酶-3和-6切割位点的蛋白水解。在HD模型中，这些不可逆抑制剂可抑制Hdh(111Q/111Q)介导的毒性，并挽救大鼠纹状体和皮质神经元免于细胞死亡。在本研究中，所鉴定的非肽类半胱天冬酶抑制剂被用于证实半胱天冬酶介导的Htt蛋白水解在HD中的作用。这些结果进一步表明半胱天冬酶是HD治疗开发的有前景的靶点。
