1] Novartis Institutes for Biomedical Research, Basel, Switzerland. [2].
Novartis Institutes for Biomedical Research, Basel, Switzerland.
Nat Neurosci. 2014 Aug;17(8):1064-72. doi: 10.1038/nn.3761. Epub 2014 Jul 13.
In Huntington's disease (HD), whether transneuronal spreading of mutant huntingtin (mHTT) occurs and its contribution to non-cell autonomous damage in brain networks is largely unknown. We found mHTT spreading in three different neural network models: human neurons integrated in the neural network of organotypic brain slices of HD mouse model, an ex vivo corticostriatal slice model and the corticostriatal pathway in vivo. Transneuronal propagation of mHTT was blocked by two different botulinum neurotoxins, each known for specifically inactivating a single critical component of the synaptic vesicle fusion machinery. Moreover, healthy human neurons in HD mouse model brain slices displayed non-cell autonomous changes in morphological integrity that were more pronounced when these neurons bore mHTT aggregates. Altogether, our findings suggest that transneuronal propagation of mHTT might be an important and underestimated contributor to the pathophysiology of HD.
在亨廷顿病（HD）中，突变型亨廷顿蛋白（mHTT）是否存在跨神经元传播，以及其对大脑网络中非细胞自主损伤的贡献在很大程度上尚不清楚。我们在三种不同的神经网络模型中发现了 mHTT 的传播：整合在 HD 小鼠模型器官型脑片神经网络中的人神经元、离体皮质纹状体切片模型和体内皮质纹状体通路。两种不同的肉毒神经毒素阻断了 mHTT 的跨神经元传播，这两种毒素都已知可以特异性失活突触小泡融合机制的单个关键成分。此外，在 HD 小鼠模型脑片中，携带 mHTT 聚集的健康人神经元表现出形态完整性的非细胞自主改变，当这些神经元携带 mHTT 聚集时，这种改变更为明显。总之，我们的发现表明 mHTT 的跨神经元传播可能是 HD 病理生理学的一个重要且被低估的贡献因素。
