Institut Pasteur, Unité de traffic membranaire et pathogenèse, 28 rue du Docteur Roux 75724 Paris, Cedex 15, France.
J Cell Sci. 2013 Aug 15;126(Pt 16):3678-85. doi: 10.1242/jcs.126086. Epub 2013 Jun 18.
Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by CAG expansion in the huntingtin gene, which adds a homopolymeric tract of polyglutamine (polyQ) to the encoded protein leading to the formation of toxic aggregates. Despite rapidly accumulating evidences supporting a role for intercellular transmission of protein aggregates, little is known about whether and how huntingtin (Htt) misfolding progresses through the brain. It has been recently reported that synthetic polyQ peptides and recombinant fragments of mutant Htt are readily internalized in cell cultures and able to seed polymerization of a reporter wild-type Htt. However, there is no direct evidence of aggregate transfer between cells and the mechanism has not been explored. By expressing recombinant fragments of mutant Htt in neuronal cells and in primary neurons, we found that aggregated fragments formed within one cell spontaneously transfer to neighbors in cell culture. We demonstrate that the intercellular spreading of the aggregates requires cell-cell contact and does not occur upon aggregate secretion. Interestingly, we found that the expression of mutant, but not wild-type Htt fragments, increases the number of tunneling nanotubes, which in turn provide an efficient mechanism of transfer.
亨廷顿病（HD）是一种由亨廷顿基因中的 CAG 扩展引起的显性遗传性神经退行性疾病，该基因导致编码蛋白中聚谷氨酰胺（polyQ）的同源多聚体增加，从而形成毒性聚集物。尽管越来越多的证据支持蛋白聚集物的细胞间传播作用，但对于亨廷顿蛋白（Htt）的错误折叠是否以及如何在大脑中进展知之甚少。最近有报道称，合成的 polyQ 肽和突变型 Htt 的重组片段在细胞培养中很容易被内吞，并能够引发报告型野生型 Htt 的聚合。然而，目前尚无细胞间聚集物转移的直接证据，其机制也尚未被探索。通过在神经元细胞和原代神经元中表达突变型 Htt 的重组片段，我们发现一个细胞内形成的聚集片段会自发地转移到细胞培养物中的相邻细胞。我们证明了细胞间聚集物的扩散需要细胞间接触，而不会在聚集物分泌时发生。有趣的是，我们发现突变型而非野生型 Htt 片段的表达会增加隧道纳米管的数量，这反过来又为转移提供了有效的机制。
