Passani L A, Bedford M T, Faber P W, McGinnis K M, Sharp A H, Gusella J F, Vonsattel J P, MacDonald M E
Molecular Neurogenetics Unit, Massachusetts General Hospital, Building 149, 13th Street, Charlestown, MA 02129, USA.
Hum Mol Genet. 2000 Sep 1;9(14):2175-82. doi: 10.1093/hmg/9.14.2175.
An elongated glutamine tract in mutant huntingtin initiates Huntington's disease (HD) pathogenesis via a novel structural property that displays neuronal selectivity, glutamine progressivity and dominance over the normal protein based on genetic criteria. As this mechanism is likely to involve a deleterious protein interaction, we have assessed the major class of huntingtin interactors comprising three WW domain proteins. These are revealed to be related spliceosome proteins (HYPA/FBP-11 and HYPC) and a transcription factor (HYPB) that implicate huntingtin in mRNA biogenesis. In HD post-mortem brain, specific antibody reagents detect each partner in HD target neurons, in association with disease-related N-terminal morphologic deposits but not with filter trapped insoluble-aggregate. Glutathione S:-transferase partner 'pull-down' assays reveal soluble, aberrantly migrating, forms of full-length mutant huntingtin specific to HD target tissue. Importantly, these novel mutant species exhibit exaggerated WW domain binding that abrogates partner association with other huntingtin isoforms. Thus, each WW domain partner's association with huntingtin fulfills HD genetic criteria, supporting a direct role in pathogenesis. Our findings indicate that modification of mutant huntingtin in target neurons may promote an abnormal interaction with one, or all, of huntingtin's WW domain partners, perhaps altering ribonucleoprotein function with toxic consequences.
突变型亨廷顿蛋白中一段延长的谷氨酰胺序列通过一种新的结构特性引发亨廷顿舞蹈病（HD）的发病机制，该特性具有神经元选择性、谷氨酰胺渐进性，且基于遗传标准对正常蛋白具有显性作用。由于这种机制可能涉及有害的蛋白质相互作用，我们评估了亨廷顿蛋白相互作用蛋白的主要类别，其中包括三种含WW结构域的蛋白质。结果发现它们是相关的剪接体蛋白（HYPA/FBP - 11和HYPC）以及一种转录因子（HYPB），这表明亨廷顿蛋白参与了mRNA生物合成。在HD患者的尸检大脑中，特异性抗体试剂在HD靶神经元中检测到每个相互作用蛋白，它们与疾病相关的N端形态学沉积物相关，但与滤膜截留的不溶性聚集体无关。谷胱甘肽S -转移酶相互作用蛋白“下拉”试验揭示了HD靶组织特有的全长突变型亨廷顿蛋白的可溶性、异常迁移形式。重要的是，这些新的突变体表现出过度的WW结构域结合，从而消除了相互作用蛋白与其他亨廷顿蛋白异构体的结合。因此，每个含WW结构域的相互作用蛋白与亨廷顿蛋白的结合符合HD的遗传标准，支持其在发病机制中发挥直接作用。我们的研究结果表明，靶神经元中突变型亨廷顿蛋白的修饰可能促进其与一种或所有亨廷顿蛋白的WW结构域相互作用蛋白发生异常相互作用，这可能会改变核糖核蛋白的功能并产生毒性后果。
