title: Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.
abstract: 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.
authors.affiliation: 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 volpicel@uab.edu.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Volpicelli-Daley
authors.affiliation: Department of Psychiatry and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Gamble
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104.
authors.forename: Christine E
authors.initials: CE
authors.lastname: Schultheiss
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104.
authors.forename: Dawn M
authors.initials: DM
authors.lastname: Riddle
authors.affiliation: Department of Neurology and Behavioral Neurobiology, University of Alabama, Birmingham, Birmingham, AL 35294.
authors.forename: Andrew B
authors.initials: AB
authors.lastname: West
authors.affiliation: Department of Pathology and Laboratory Medicine, Institute on Aging, and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104.
authors.forename: Virginia M-Y
authors.initials: VM
authors.lastname: Lee
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport; D002478:Cells, Cultured; D011992:Endosomes / Q000378:metabolism* / Q000473:pathology; D016631:Lewy Bodies; D051379:Mice; D010300:Parkinson Disease / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D066329:Protein Aggregates; D021381:Protein Transport; D020813:Receptor, trkB / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D000682:Amyloid; D066329:Protein Aggregates; D051844:alpha-Synuclein; D020813:Receptor, trkB