Exosome secretion is a key pathway for clearance of pathological TDP-43.
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-43A315Tmutant. 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.
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Yohei
Y
Iguchi
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Lara
L
Eid
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Martin
M
Parent
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Geneviève
G
Soucy
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Christine
C
Bareil
3 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Yuichi
Y
Riku
3 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Kaori
K
Kawai
3 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Shinnosuke
S
Takagi
4 Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Aichi, Japan.
Mari
M
Yoshida
3 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Masahisa
M
Katsuno
3 Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan.
Gen
G
Sobue
1 Centre de recherche de l'Institut universitaire en santé mentale de Québec, Quebec City, Qc, Canada jean-pierre.julien@fmed.ulaval.ca.|2 Department of Psychiatry and Neuroscience, Université Laval, Quebec City, Qc, Canada.
Jean-Pierre
JP
Julien
D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001597:Benzylidene Compounds / Q000494:pharmacology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D055354:Exosomes / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013108:Sphingomyelin Phosphodiesterase / Q000187:drug effects*; D057177:TDP-43 Proteinopathies / Q000188:drug therapy / Q000378:metabolism*
D000814:Aniline Compounds; D001597:Benzylidene Compounds; D004268:DNA-Binding Proteins; C468773:GW 4869; C000598624:TARDBP protein, human; C491484:SMPD3 protein, human; D013108:Sphingomyelin Phosphodiesterase
TDP-43; amyotrophic lateral sclerosis; exosome; neutral sphingomyelinase 2 inhibition
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