Pathological Axonal Death through a MAPK Cascade that Triggers a Local Energy Deficit

Yang, Jing; Wu, Zhuhao; Renier, Nicolas; Simon, David; Uryu, Kunihiro; Park, David; Greer, Peter A.; Tournier, Cathy; Davis, Roger J.; Tessier‐Lavigne, Marc

doi:10.1016/j.cell.2014.11.053

Cited by 254 publications

(319 citation statements)

References 32 publications

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“…Here, an accumulation of cytosolic calcium activates calpain proteases that in turn activate killer aspartyl proteases leading to cell destruction 45 . A recent study using mammalian models demonstrated that axonal injury phenotypes mediated by Sarm1 also require calpain proteases 46 . Thus, there may be a convergence of the TIR-1/Sarm1 pathway in regulating motor neuron degeneration via calpain proteases in ALS.…”

Section: Discussionmentioning

confidence: 99%

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

Vérièpe

Fossouo²,

Parker

2015

Nat Commun

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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.

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Section: Discussionmentioning

confidence: 99%

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

Vérièpe

Fossouo²,

Parker

2015

Nat Commun

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“…These findings support a model wherein N-terminal autoinhibition of TIR activity is mediated by direct binding between the N terminus and the TIR domain. Discussion SARM1 activation in response to neuronal injury evokes a rapid consumption of NAD + followed by a decline in ATP that ultimately leads to local axonal degeneration or neuronal cell death (4,13). Although the molecular signaling pathways underlying SARM1-dependent neuronal destruction are still being defined, dimerization of the TIR domain of SARM1 is sufficient to stimulate NAD + loss and neuronal death.…”

Section: Mutant Sarm1 (K597e) Acts As a Dominant Negative And Blocksmentioning

confidence: 99%

“…In addition, axon degeneration can occur through mechanistically distinct pathways from Wallerian degeneration (36). Importantly, tir-1 acts upstream of a MAPK signaling pathway, a function that is also conserved, because vertebrate SARM1 activates a MAPK signal during injury-induced axon degeneration (11,13,20,36). Hence, both signaling and NAD + -depleting functions of the SARM1 TIR domain are conserved.…”

Section: The Sarm1 Tir Domain Is a Conserved Executioner Of Neuronalmentioning

confidence: 99%

“…SARM1 possesses a Toll/interleukin receptor (TIR) domain that is required for SARM1-dependent axon degeneration and cell death. Recently, others and we demonstrated that enforced dimerization of the SARM1 TIR domain is sufficient to induce local axon degeneration (3,4,13). Tandem sterile alpha motif (SAM) domains mediate SARM1 multimerization, and hence are required for SARM1 activity.…”

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confidence: 99%

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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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“…More recent evidence indicates that NMNAT2 inhibits the depletion of ATP triggered by the activation of sterile alpha and Toll/interleukin‐1 receptor motif‐containing protein‐1 (SARM1) following axotomy, a prodegenerative NADase involved in axonal degeneration 50, 51. Interestingly, calpain inhibition or calpastatin overexpression did not prevent the energy depletion observed after axotomy 52. Taken together these observations suggest that NMNATs functions upstream to the cellular cascade that triggers the depletion of ATP and subsequent activation of the calpain‐calpastatin degenerative cascade following axotomy.…”

Section: Discussionmentioning

confidence: 99%

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

Galindo

Greenberg

Araki

et al. 2017

Ann Clin Transl Neurol

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ObjectiveTo determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase‐3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia‐ischemia (H‐I) and reducing glutamate receptor‐mediated excitotoxic neurodegeneration of immature neurons.MethodsUsing NMNAT3‐overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H‐I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3‐dependent neuroprotection. Using AAV8‐mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor‐mediated excitotoxicity.ResultsNMNAT3 mRNA and protein levels increased after neonatal H‐I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase‐3 activity and calpain‐mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.ConclusionsOur observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H‐I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic‐ischemic encephalopathy.

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Pathological Axonal Death through a MAPK Cascade that Triggers a Local Energy Deficit

Cited by 254 publications

References 32 publications

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

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

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

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

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Pathological Axonal Death through a MAPK Cascade that Triggers a Local Energy Deficit

Cited by 254 publications

References 32 publications

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

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

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

NMNAT3 is protective against the effects of neonatal cerebral hypoxia‐ischemia

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