Centre Hospitalier Universitaire de Québec Research Center; Departments of Psychiatry and Neurosciences.
Ann Neurol. 2014 Jul;76(1):31-42. doi: 10.1002/ana.24174. Epub 2014 Jun 6.
Huntington disease (HD) is caused by a genetically encoded pathological protein (mutant huntingtin [mHtt]), which is thought to exert its effects in a cell-autonomous manner. Here, we tested the hypothesis that mHtt is capable of spreading within cerebral tissue by examining genetically unrelated fetal neural allografts within the brains of patients with advancing HD.
The presence of mHtt aggregates within the grafted tissue was confirmed using 3 different types of microscopy (bright-field, fluorescence, and electron), 2 additional techniques consisting of Western immunoblotting and infrared spectroscopy, and 4 distinct antibodies targeting different epitopes of mHtt aggregates.
We describe the presence of mHtt aggregates within intracerebral allografts of striatal tissue in 3 HD patients who received their transplants approximately 1 decade earlier and then died secondary to the progression of their disease. The mHtt(+) aggregates were observed in the extracellular matrix of the transplanted tissue, whereas in the host brain they were seen in neurons, neuropil, extracellular matrix, and blood vessels.
This is the first demonstration of the presence of mHtt in genetically normal and unrelated allografted neural tissue transplanted into the brain of affected HD patients. These observations raise questions on protein spread in monogenic neurodegenerative disorders of the central nervous system characterized by the formation of mutant protein oligomers/aggregates.
亨廷顿病（HD）是由遗传编码的病理性蛋白（突变型亨廷顿蛋白[mHtt]）引起的，据认为该蛋白以细胞自主的方式发挥作用。在这里，我们通过检查在进展性 HD 患者大脑内的遗传上无关的胎儿神经同种异体移植物，检验 mHtt 有能力在脑组织内传播的假说。
使用 3 种不同类型的显微镜（明场、荧光和电子显微镜）、2 种包括 Western 免疫印迹和红外光谱学的额外技术以及 4 种针对 mHtt 聚集物不同表位的独特抗体，确认移植组织内 mHtt 聚集物的存在。
我们描述了 3 名 HD 患者的脑内同种异体纹状体移植物内存在 mHtt 聚集物，这些患者在大约 10 年前接受了移植，然后由于疾病的进展而死亡。mHtt(+)聚集物在移植组织的细胞外基质中观察到，而在宿主大脑中则在神经元、神经突、细胞外基质和血管中观察到。
这是首例在受影响的 HD 患者大脑内移植的遗传正常和无关同种异体神经组织中存在 mHtt 的证明。这些观察结果引发了关于以形成突变型蛋白寡聚体/聚集物为特征的中枢神经系统单基因神经退行性疾病中蛋白传播的问题。
