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

TitleExosome secretion is a key pathway for clearance of pathological TDP-43.
Publication TypeJournal Article
Year of Publication2016
AuteursIguchi, Y, Eid, L, Parent, M, Soucy, G, Bareil, C, Riku, Y, Kawai, K, Takagi, S, Yoshida, M, Katsuno, M, Sobue, G, Julien, J-P
JournalBrain
Volume139
IssuePt 12
Pagination3187-3201
Date Published2016 Dec
ISSN1460-2156
KeywordsAniline Compounds, Animals, Behavior, Animal, Benzylidene Compounds, Cell Line, Disease Models, Animal, DNA-Binding Proteins, Exosomes, Humans, Mice, Mice, Transgenic, Sphingomyelin Phosphodiesterase, TDP-43 Proteinopathies
Abstract

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-43A315T 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.

DOI10.1093/brain/aww237
Alternate JournalBrain
PubMed ID27679482