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Nat Commun. 2015 Jun 10;6:7319. doi: 10.1038/ncomms8319.

Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons.

Author information

1
1] CRCHUM, Montréal, Québec, Canada H2X 0A9 [2] Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
2
CRCHUM, Montréal, Québec, Canada H2X 0A9.
3
1] CRCHUM, Montréal, Québec, Canada H2X 0A9 [2] Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada H3C 3J7 [3] Département de neurosciences, Université de Montréal, Montréal, Québec, Canada H3C 3J7.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease thought to employ cell non-autonomous mechanisms where neuronal injury engages immune responses to influence disease progression. Here we show that the expression of mutant proteins causative for ALS in Caenorhabditis elegans motor neurons induces an innate immune response via TIR-1/Sarm1. Loss of function mutations in tir-1, associated downstream kinases, and the transcription factor atf-7 all suppress motor neuron degeneration. The neurosecretory proteins UNC-13 and UNC-31 are required for induction of the immune response as well as the degeneration of motor neurons. The human orthologue of UNC-13, UNC13A, has been identified as a genetic modifier of survival in ALS, and we provide functional evidence of UNC-13/UNC13A in regulating motor neuron degeneration. We propose that the innate immune system reacts to the presence of mutant proteins as a contagion, recruiting a pathogen resistance response that is ultimately harmful and drives progressive neurodegeneration.

PMID:
26059317
DOI:
10.1038/ncomms8319
[Indexed for MEDLINE]

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