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

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 whic...

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Autores principales: Volpicelli-Daley, Laura A., Gamble, Karen L., Schultheiss, Christine E., Riddle, Dawn M., West, Andrew B., Lee, Virginia M.-Y.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society for Cell Biology 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263445/
https://www.ncbi.nlm.nih.gov/pubmed/25298402
http://dx.doi.org/10.1091/mbc.E14-02-0741
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author Volpicelli-Daley, Laura A.
Gamble, Karen L.
Schultheiss, Christine E.
Riddle, Dawn M.
West, Andrew B.
Lee, Virginia M.-Y.
author_facet Volpicelli-Daley, Laura A.
Gamble, Karen L.
Schultheiss, Christine E.
Riddle, Dawn M.
West, Andrew B.
Lee, Virginia M.-Y.
author_sort Volpicelli-Daley, Laura A.
collection PubMed
description 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.
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spelling pubmed-42634452015-03-02 Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes Volpicelli-Daley, Laura A. Gamble, Karen L. Schultheiss, Christine E. Riddle, Dawn M. West, Andrew B. Lee, Virginia M.-Y. Mol Biol Cell Articles 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. The American Society for Cell Biology 2014-12-15 /pmc/articles/PMC4263445/ /pubmed/25298402 http://dx.doi.org/10.1091/mbc.E14-02-0741 Text en © 2014 Volpicelli-Daley et al. This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0). “ASCB®,” “The American Society for Cell Biology®,” and “Molecular Biology of the Cell®” are registered trademarks of The American Society for Cell Biology.
spellingShingle Articles
Volpicelli-Daley, Laura A.
Gamble, Karen L.
Schultheiss, Christine E.
Riddle, Dawn M.
West, Andrew B.
Lee, Virginia M.-Y.
Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title_full Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title_fullStr Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title_full_unstemmed Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title_short Formation of α-synuclein Lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
title_sort formation of α-synuclein lewy neurite–like aggregates in axons impedes the transport of distinct endosomes
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4263445/
https://www.ncbi.nlm.nih.gov/pubmed/25298402
http://dx.doi.org/10.1091/mbc.E14-02-0741
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