Formation of α-synuclein Lewy neurite-like aggregates in axons impedes the transport of distinct endosomes.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Volpicelli-Daley, LA; Gamble, KL; Schultheiss, CE; Riddle, DM; West, AB; Lee, VM-Y

Published Date

  • December 15, 2014

Published In

Volume / Issue

  • 25 / 25

Start / End Page

  • 4010 - 4023

PubMed ID

  • 25298402

Pubmed Central ID

  • 25298402

Electronic International Standard Serial Number (EISSN)

  • 1939-4586

Digital Object Identifier (DOI)

  • 10.1091/mbc.E14-02-0741

Language

  • eng

Conference Location

  • United States