title: Neurodegeneration in C. elegans models of ALS requires TIR-1/Sarm1 immune pathway activation in neurons.
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.
authors.affiliation: 1] CRCHUM, Montréal, Québec, Canada H2X 0A9 [2] Département de pathologie et biologie cellulaire, Université de Montréal, Montréal, Québec, Canada H3C 3J7.
authors.forename: Julie
authors.initials: J
authors.lastname: Vérièpe
authors.affiliation: CRCHUM, Montréal, Québec, Canada H2X 0A9.
authors.forename: Lucresse
authors.initials: L
authors.lastname: Fossouo
authors.affiliation: 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.
authors.forename: J Alex
authors.identifier: 0000000233332445
authors.initials: JA
authors.lastname: Parker
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000276:immunology / Q000473:pathology*; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000276:immunology*; D029742:Caenorhabditis elegans Proteins / Q000276:immunology*; D004195:Disease Models, Animal; D007113:Immunity, Innate; D009046:Motor Neurons / Q000473:pathology; D009474:Neurons / Q000276:immunology*; D043562:Receptors, G-Protein-Coupled / Q000276:immunology*
chemical_list: D029742:Caenorhabditis elegans Proteins; D043562:Receptors, G-Protein-Coupled; C485906:tir-1 protein, C elegans