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

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  • Julie Vérièpe

    (CRCHUM
    Université de Montréal)

  • Lucresse Fossouo

    (CRCHUM)

  • J Alex Parker

    (CRCHUM
    Université de Montréal
    Université de Montréal)

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.

Suggested Citation

  • Julie Vérièpe & Lucresse Fossouo & J Alex Parker, 2015. "Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons," Nature Communications, Nature, vol. 6(1), pages 1-9, November.
    • Handle: RePEc:nat:natcom:v:6:y:2015:i:1:d:10.1038_ncomms8319
    DOI: 10.1038/ncomms8319
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    Cited by:

    1. Wang Yuan & Yi M. Weaver & Svetlana Earnest & Clinton A. Taylor & Melanie H. Cobb & Benjamin P. Weaver, 2023. "Modulating p38 MAPK signaling by proteostasis mechanisms supports tissue integrity during growth and aging," Nature Communications, Nature, vol. 14(1), pages 1-16, December.

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