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

Vérièpe, Julie; Fossouo, Lucresse; Parker, J. Alex

doi:10.1038/ncomms8319

Cited by 70 publications

(67 citation statements)

References 49 publications

(67 reference statements)

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“…Interestingly, this finding appears to be in contrast with a recent report in Caenorhabditis elegans describing that TIR-1, the nematode Sarm1 ortholog, acts downstream of TDP-43 toxicity in neurons (although this may not be a cell autonomous effect) [12], and the finding that fly Wallenda, a potential Wallerian degeneration regulator [13], can modify TDP-43 toxicity [8].…”

contrasting

confidence: 61%

Neurodegeneration: A Leg Up on TDP-43

Figley

Gitler

2015

Current Biology

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contrasting

confidence: 61%

Neurodegeneration: A Leg Up on TDP-43

Figley

Gitler

2015

Current Biology

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“…To identify elements within the SARM1 TIR domain responsible for NAD + loss and cell death, we first investigated whether this TIR activity is conserved in a distant SARM1 relative. The SARM1 ortholog in C. elegans, tir-1, is implicated in nonapoptotic cell death in development and motor neuron degeneration in a model of ALS (18,19), suggesting a conserved role in neurodegeneration. However, tir-1 regulates developmental patterning in the nervous system as well as stimulating innate immune signaling in response to pathogens (11,20,21), two activities that appear inconsistent with the neurodestructive properties of human SARM1.…”

Section: Resultsmentioning

confidence: 99%

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Summers

Gibson

DiAntonio

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

117

125

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Axon injury in response to trauma or disease stimulates a selfdestruction program that promotes the localized clearance of damaged axon segments. Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) is an evolutionarily conserved executioner of this degeneration cascade, also known as Wallerian degeneration; however, the mechanism of SARM1-dependent neuronal destruction is still obscure. SARM1 possesses a TIR domain that is necessary for SARM1 activity. In other proteins, dimerized TIR domains serve as scaffolds for innate immune signaling. In contrast, dimerization of the SARM1 TIR domain promotes consumption of the essential metabolite NAD + and induces neuronal destruction. This activity is unique to the SARM1 TIR domain, yet the structural elements that enable this activity are unknown. In this study, we identify fundamental properties of the SARM1 TIR domain that promote NAD + loss and axon degeneration. Dimerization of the TIR domain from the Caenorhabditis elegans SARM1 ortholog TIR-1 leads to NAD + loss and neuronal death, indicating these activities are an evolutionarily conserved feature of SARM1 function. Detailed analysis of sequence homology identifies canonical TIR motifs as well as a SARM1-specific (SS) loop that are required for NAD + loss and axon degeneration. Furthermore, we identify a residue in the SARM1 BB loop that is dispensable for TIR activity yet required for injury-induced activation of full-length SARM1, suggesting that SARM1 function requires multidomain interactions. Indeed, we identify a physical interaction between the autoinhibitory N terminus and the TIR domain of SARM1, revealing a previously unrecognized direct connection between these domains that we propose mediates autoinhibition and activation upon injury.A xon degeneration in response to injury or disease is a hallmark of neurological disorders of the peripheral and central nervous systems. Akin to programmed cell death pathways, such as apoptosis, axon injury in response to disease or trauma stimulates a local signaling cascade that executes destruction of the injured axon segment (1). Despite growing attention, the molecular details of this prodegenerative cascade are still unclear. A more substantial understanding of the molecular factors that participate in this axon destructive process will likely provide new therapeutic strategies for peripheral neuropathies and other neurodegenerative conditions.Genetic screens in invertebrate and vertebrate model systems identified the Sterile alpha and Toll/interleukin receptor (TIR) motif-containing protein 1 (SARM1) as a conserved, fundamental executioner of pathological axon destruction (2, 3). After nerve injury, SARM1 is required for the precipitous loss of the metabolite NAD + (4). Augmenting NAD + biosynthetic pathways protects injured axons from degeneration, suggesting this step is crucial in axonal breakdown (5, 6). In addition to local axon degeneration, SARM1 promotes neuronal cell death in response to mitochondrial toxins, oxygen gluc...

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“…Moreover, endogenous SARM1 promotes neuronal cell death in response to various insults including mitochondrial poisons, oxygen-glucose deprivation, and neurotropic viruses (Kim et al, 2007; Mukherjee et al, 2013; Summers et al, 2014). This function is conserved in C. elegans —the SARM1 ortholog tir-1 promotes non-apoptotic developmental cell death, death triggered by anoxia, and motor neuron degeneration in an ALS model (Blum et al, 2012; Hayakawa et al, 2011; Vérièpe et al, 2015). Hence, SARM1 is a flexible executioner, able to trigger local axon loss or global neuron death.…”

Section: Sarmoptosis: a Destructive Role For Sarm1 Beyond The Axonmentioning

confidence: 99%

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

Gerdts

Summers

Milbrandt

et al. 2016

Neuron

290

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Wallerian axon degeneration is a form of programmed subcellular death that promotes axon breakdown in disease and injury. Active degeneration requires SARM1 and MAP kinases including DLK, while the NAD+ synthetic enzyme NMNAT2 prevents degeneration. New studies reveal that these pathways cooperate in a locally-mediated axon destruction program with NAD+ metabolism playing a central role. Here, we review the biology of Wallerian type axon degeneration and discuss the most recent findings with special emphasis on critical signaling events and their potential as therapeutic targets for axonopathy.

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

Cited by 70 publications

References 49 publications

Neurodegeneration: A Leg Up on TDP-43

Neurodegeneration: A Leg Up on TDP-43

SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

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

Cited by 70 publications

References 49 publications

Neurodegeneration: A Leg Up on TDP-43

Neurodegeneration: A Leg Up on TDP-43

SARM1-specific motifs in the TIR domain enable NAD + loss and regulate injury-induced SARM1 activation

Axon Self-Destruction: New Links among SARM1, MAPKs, and NAD+ Metabolism

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SARM1-specific motifs in the TIR domain enable NAD ⁺ loss and regulate injury-induced SARM1 activation