Monteiro Olivia, Chen Changwei, Bingham Ryan, Argyrou Argyrides, Buxton Rachel, Pancevac Jönsson Christina, Jones Emma, Bridges Angela, Gatfield Kelly, Krauß Sybille, Lambert Jeremy, Langston Rosamund, Schweiger Susann, Uings Iain
Division of Neuroscience, University of Dundee, UK.
Platform Technology and Sciences,GlaxoSmithKline, UK.
Neurosci Lett. 2018 Apr 23;673:44-50. doi: 10.1016/j.neulet.2018.02.061. Epub 2018 Feb 27.
Expression of mutant Huntingtin (HTT) protein is central to the pathophysiology of Huntington's Disease (HD). The E3 ubiquitin ligase MID1 appears to have a key role in facilitating translation of the mutant HTT mRNA suggesting that interference with the function of this complex could be an attractive therapeutic approach. Here we describe a peptide that is able to disrupt the interaction between MID1 and the α4 protein, a regulatory subunit of protein phosphatase 2A (PP2A). By fusing this peptide to a sequence from the HIV-TAT protein we demonstrate that the peptide can disrupt the interaction within cells and show that this results in a decrease in levels of ribosomal S6 phosphorylation and HTT expression in cultures of cerebellar granule neurones derived from Hdh mice. This data serves to validate this pathway and paves the way for the discovery of small molecule inhibitors of this interaction as potential therapies for HD.
突变型亨廷顿蛋白（HTT）的表达是亨廷顿舞蹈症（HD）病理生理学的核心。E3泛素连接酶MID1似乎在促进突变型HTT mRNA的翻译中起关键作用，这表明干扰该复合物的功能可能是一种有吸引力的治疗方法。在这里，我们描述了一种能够破坏MID1与α4蛋白（蛋白磷酸酶2A（PP2A）的调节亚基）之间相互作用的肽。通过将该肽与HIV-TAT蛋白的序列融合，我们证明该肽可以破坏细胞内的相互作用，并表明这导致来自Hdh小鼠的小脑颗粒神经元培养物中核糖体S6磷酸化水平和HTT表达降低。这些数据有助于验证该途径，并为发现作为HD潜在疗法的这种相互作用的小分子抑制剂铺平道路。
