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Exosome secretion is a key pathway for clearance of pathological TDP-43

Brain (London, England : 1878), 2016-12, Vol.139 (Pt 12), p.3187-3201 [Peer Reviewed Journal]

The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com. ;The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2016 ;ISSN: 0006-8950 ;EISSN: 1460-2156 ;DOI: 10.1093/brain/aww237 ;PMID: 27679482

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Title:
Exosome secretion is a key pathway for clearance of pathological TDP-43
Author: Iguchi, Yohei ; Eid, Lara ; Parent, Martin ; Soucy, Geneviève ; Bareil, Christine ; Riku, Yuichi ; Kawai, Kaori ; Takagi, Shinnosuke ; Yoshida, Mari ; Katsuno, Masahisa ; Sobue, Gen ; Julien, Jean-Pierre
Subjects: Aniline Compounds - pharmacology ; Animals ; Behavior, Animal - drug effects ; Benzylidene Compounds - pharmacology ; Cell Line ; Disease Models, Animal ; DNA-Binding Proteins - metabolism ; Editor's Choice ; Exosomes - metabolism ; Humans ; Mice ; Mice, Transgenic ; Original ; Sphingomyelin Phosphodiesterase - drug effects ; TDP-43 Proteinopathies - drug therapy ; TDP-43 Proteinopathies - metabolism
Is Part Of: Brain (London, England : 1878), 2016-12, Vol.139 (Pt 12), p.3187-3201
Description: Cytoplasmic TDP-43 aggregation is a pathological hallmark of amyotrophic lateral sclerosis and frontotemporal lobar degeneration. Here we investigated the role of exosomes in the secretion and propagation of TDP-43 aggregates. TDP-43 was detected in secreted exosomes from Neuro2a cells and primary neurons but not from astrocytes or microglia. Evidence is presented that protein aggregation and autophagy inhibition are factors that promote exosomal secretion of TDP-43. We also report that levels of exosomal TDP-43 full length and C-terminal fragment species are upregulated in human amyotrophic lateral sclerosis brains. Exposure of Neuro2a cells to exosomes from amyotrophic lateral sclerosis brain, but not from control brain, caused cytoplasmic redistribution of TDP-43, suggesting that secreted exosomes might contribute to propagation of TDP-43 proteinopathy. Yet, inhibition of exosome secretion by inactivation of neutral sphingomyelinase 2 with GW4869 or by silencing RAB27A provoked formation of TDP-43 aggregates in Neuro2a cells. Moreover, administration of GW4869 exacerbated the disease phenotypes of transgenic mice expressing human TDP-43 mutant. Thus, even though results suggest that exosomes containing pathological TDP-43 may play a key role in the propagation of TDP-43 proteinopathy, a therapeutic strategy for amyotrophic lateral sclerosis based on inhibition of exosome production would seem inappropriate, as in vivo data suggest that exosome secretion plays an overall beneficial role in neuronal clearance of pathological TDP-43.
Publisher: England: Oxford University Press
Language: English
Identifier: ISSN: 0006-8950
EISSN: 1460-2156
DOI: 10.1093/brain/aww237
PMID: 27679482
Source: Geneva Foundation Free Medical Journals at publisher websites
MEDLINE
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Exosome secretion is a key pathway for clearance of pathological TDP-43

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