Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.
Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.
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DOI：
10.1091/mbc.e14-02-0741
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发表时间：
2014-12-15
影响因子：
3.3
通讯作者：
Lee VM
中科院分区：
文献类型：
--
作者：
Volpicelli-Daley LA;Gamble KL;Schultheiss CE;Riddle DM;West AB;Lee VM
轴突的病理性α-突触核蛋白包涵体损害含有Rab7和TrkB受体的核内体以及自噬体的运输。突触素和线粒体的运输没有改变。轴突转运的选择性缺陷可能与帕金森病的病因有关，并对治疗具有重要意义。α-突触核蛋白（α-syn）聚集在帕金森病和其他突触核蛋白病的神经元中。即使在疾病的早期阶段，这些内含物也主要定位于轴突，但它们对轴突功能的影响仍然未知。在此之前，我们建立了一个模型，将预先形成的α-syn原纤维添加到原代神经元中，形成了由内源性表达的α-syn构建的不溶性α-syn包涵体，这些包涵体与人类病变大脑中发现的路易神经突的神经病理表型密切相关。通过活细胞成像，我们发现固定的α-syn包涵体在轴突中聚集，这是由于位于活动α-syn阳性囊泡上的α-syn的募集。超微结构分析和实时成像显示α-syn积聚不会引起轴突运输的全身性缺陷；包涵体不填满轴突细胞质，不破坏微管细胞骨架，也不影响突触素或线粒体的运输。然而，α-syn聚集体损害了含有Rab7和TrkB受体的核内体以及自噬体的运输。此外，TrkB受体相关的信号分子pERK5在α-syn聚集的神经元中积累。因此α-syn病理损害了信号传导和降解细胞器的轴突运输。α-syn积累的这些早期效应可以预测神经退行性过程的干预点。
Pathological α-synuclein inclusions in axons impair transport of Rab7 and TrkB receptor-containing endosomes, as well as autophagosomes. Transport of synaptophysin and mitochondria is unaltered. Selective defects in axonal transport may contribute to the etiology of Parkinson's disease and have important implications for treatment. Aggregates of α-synuclein (α-syn) accumulate in neurons in Parkinson's disease and other synucleinopathies. These inclusions predominantly localize to axons even in the early stages of the disease, but their affect on axon function has remained unknown. Previously we established a model in which the addition of preformed α-syn fibrils to primary neurons seeds formation of insoluble α-syn inclusions built from endogenously expressed α-syn that closely recapitulate the neuropathological phenotypes of Lewy neurites found in human diseased brains. Here we show, using live-cell imaging, that immobile α-syn inclusions accumulate in axons from the recruitment of α-syn located on mobile α-syn–positive vesicles. Ultrastructural analyses and live imaging demonstrate that α-syn accumulations do not cause a generalized defect in axonal transport; the inclusions do not fill the axonal cytoplasm, disrupt the microtubule cytoskeleton, or affect the transport of synaptophysin or mitochondria. However, the α-syn aggregates impair the transport of Rab7 and TrkB receptor–containing endosomes, as well as autophagosomes. In addition, the TrkB receptor–associated signaling molecule pERK5 accumulates in α-syn aggregate–bearing neurons. Thus α-syn pathology impairs axonal transport of signaling and degradative organelles. These early effects of α-syn accumulations may predict points of intervention in the neurodegenerative process.