Accumulating evidence highlights the potential role of mixed proteinopathies (i.e., abnormal protein aggregation) in the development of clinical manifestations of neurodegenerative diseases (NDD). Huntington’s disease (HD) is an inherited NDD caused by autosomal-dominant expanded CAG trinucleotide repeat mutation in the gene coding for Huntingtin (Htt). Previous studies have suggested the coexistence of phosphorylated-Tau, α-synuclein (α-Syn) and TAR DNA-binding protein 43 (TDP-43) inclusions in HD. However, definite evidence that HD pathology in humans can be accompanied by other proteinopathies is still lacking. Using human post-mortem putamen samples from 31 controls and 56 HD individuals, we performed biochemical analyses of the expression, oligomerization and aggregation of Tau, α-Syn, TDP-43, and Amyloid precursor protein (APP)/Aβ. In HD brain, we observed reduced soluble protein (but not mRNA) levels of Htt, α-Syn, and Tau. Our results also support abnormal phosphorylation of Tau in more advanced stages of disease. Aberrant splicing of Tau exons 2, 3 (exclusion) and 10 (inclusion) was also detected in HD patients, leading to higher 0N4R and lower 1N3R isoforms. Finally, following formic acid extraction, we observed increased aggregation of TDP-43, α-Syn, and phosphorylated-Tau during HD progression. Notably, we observed that 88% of HD patients with Vonsattel grade 4 neuropathology displayed at least one non-Htt proteinopathy compared to 29% in controls. Interestingly, α-Syn aggregation correlated with Htt, TDP-43 and phosphorylated-Tau in HD but not in controls. The impact of this work is twofold: (1) it provides compelling evidences that Tau, α-Syn and TDP-43 proteinopathies are increased in HD, and (2) it suggests the involvement of common mechanisms leading to abnormal accumulation of aggregation-prone proteins in NDD. Further studies will be needed to decipher the impact of these proteinopathies on clinical manifestation of HD.

越来越多的证据凸显了混合蛋白质病（即异常蛋白质聚集）在神经退行性疾病（NDD）临床表现发展中的潜在作用。亨廷顿舞蹈病（HD）是一种遗传性NDD，是由编码亨廷顿（Htt）的基因中常染色体显性扩展的CAG三核苷酸重复突变引起的。先前的研究表明，HD中磷酸化的Tau，α-突触核蛋白（α-Syn）和TAR DNA结合蛋白43（TDP-43）夹杂物并存。但是，仍然缺乏确定人类HD病理可伴有其他蛋白病变的确切证据。我们使用来自31个对照和56个HD个体的人体尸检样品，我们对Tau，α-Syn，TDP-43和淀粉样前体蛋白（APP）/Aβ的表达，寡聚和聚集进行了生化分析。在高清大脑中，我们观察到Htt，α-Syn和Tau的可溶性蛋白（而非mRNA）水平降低。我们的结果还支持在疾病的更晚期阶段Tau的异常磷酸化。在HD患者中也检测到Tau外显子2、3（排除）和10（包括）的异常剪接，导致较高的0N4R和较低的1N3R亚型。最后，在甲酸提取后，我们观察到HD进程中TDP-43，α-Syn和磷酸化Tau的聚集增加。值得注意的是，我们观察到88％患有Vonsattel 4级神经病理学的HD患者表现出至少一种非Htt蛋白病，而对照组为29％。有趣的是，HD中的α-Syn聚集与Htt，TDP-43和磷酸化的Tau相关，但与对照无关。这项工作的影响是双重的：（1）它提供了令人信服的证据，证明Tau，HD中α-Syn和TDP-43蛋白病增加，并且（2）表明参与导致NDD中易于聚集蛋白异常聚集的常见机制。需要进一步的研究来破译这些蛋白病对HD临床表现的影响。