Volpicelli-Daley Laura A, Gamble Karen L, Schultheiss Christine E, Riddle Dawn M, West Andrew B, Lee Virginia M-Y
Department of Neurology and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294 Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104
Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294.
Mol Biol Cell. 2014 Dec 15;25(25):4010-23. doi: 10.1091/mbc.E14-02-0741. Epub 2014 Oct 8.
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.
α-突触核蛋白（α-syn）聚集体在帕金森病和其他突触核蛋白病的神经元中积聚。即使在疾病的早期阶段，这些包涵体也主要定位于轴突，但其对轴突功能的影响尚不清楚。此前我们建立了一个模型，向原代神经元中添加预先形成的α-syn原纤维，可引发由内源性表达的α-syn形成的不溶性α-syn包涵体的形成，该模型能紧密重现人类患病大脑中路易神经突的神经病理学表型。在此我们利用活细胞成像显示，静止的α-syn包涵体通过募集位于移动的α-syn阳性囊泡上的α-syn而在轴突中积聚。超微结构分析和实时成像表明，α-syn积聚不会导致轴突运输出现普遍缺陷；这些包涵体不会充满轴突细胞质、破坏微管细胞骨架或影响突触素或线粒体的运输。然而，α-syn聚集体会损害含Rab7和TrkB受体的内体以及自噬体的运输。此外，TrkB受体相关信号分子pERK5在含有α-syn聚集体的神经元中积聚。因此，α-syn病理学损害了信号传导和降解细胞器的轴突运输。α-syn积聚的这些早期影响可能预示着神经退行性过程中的干预点。
