Abounit Saïda, Bousset Luc, Loria Frida, Zhu Seng, de Chaumont Fabrice, Pieri Laura, Olivo-Marin Jean-Christophe, Melki Ronald, Zurzolo Chiara
Institut Pasteur, Unité Trafic Membranaire et Pathogénèse, Paris Cedex 15, France.
Paris-Saclay Institute of Neuroscience, CNRS, Gif-sur-Yvette, France.
EMBO J. 2016 Oct 4;35(19):2120-2138. doi: 10.15252/embj.201593411. Epub 2016 Aug 22.
Synucleinopathies such as Parkinson's disease are characterized by the pathological deposition of misfolded α-synuclein aggregates into inclusions throughout the central and peripheral nervous system. Mounting evidence suggests that intercellular propagation of α-synuclein aggregates may contribute to the neuropathology; however, the mechanism by which spread occurs is not fully understood. By using quantitative fluorescence microscopy with co-cultured neurons, here we show that α-synuclein fibrils efficiently transfer from donor to acceptor cells through tunneling nanotubes (TNTs) inside lysosomal vesicles. Following transfer through TNTs, α-synuclein fibrils are able to seed soluble α-synuclein aggregation in the cytosol of acceptor cells. We propose that donor cells overloaded with α-synuclein aggregates in lysosomes dispose of this material by hijacking TNT-mediated intercellular trafficking. Our findings thus reveal a possible novel role of TNTs and lysosomes in the progression of synucleinopathies.
诸如帕金森病之类的突触核蛋白病的特征是错误折叠的α-突触核蛋白聚集体在中枢和外周神经系统中病理性沉积形成包涵体。越来越多的证据表明，α-突触核蛋白聚集体的细胞间传播可能导致神经病理学；然而，其传播机制尚未完全明确。通过对共培养神经元使用定量荧光显微镜，我们在此表明，α-突触核蛋白原纤维通过溶酶体囊泡内的隧道纳米管（TNTs）从供体细胞高效转移至受体细胞。通过TNTs转移后，α-突触核蛋白原纤维能够在受体细胞的胞质溶胶中引发可溶性α-突触核蛋白聚集。我们提出，溶酶体中α-突触核蛋白聚集体过载的供体细胞通过劫持TNT介导的细胞间运输来处理这些物质。因此，我们的研究结果揭示了TNTs和溶酶体在突触核蛋白病进展中可能具有的新作用。
