SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites

Angeletti, Carlo Alberto; Amici, Adolfo; Gilley, Jonathan; Loreto, Andrea; Trapanotto, Antonio G.; Antoniou, Christina; Merlini, Elisa; Coleman, Michael P.; Orsomando, Giuseppe

doi:10.1016/j.isci.2022.103812

Cited by 58 publications

(104 citation statements)

References 79 publications

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“…Sarm1 (Sterile alpha and TIR motif containing1) is a NAD(P) glycohydrolase and a prominent executor of programmed axon death (Angeletti et al, 2022; Hopkins et al, 2021). Compelling evidence shows that an increase in NMN to NAD+ ratio after NMNAT2 loss activates Sarm1 to trigger axon degeneration (Figley et al, 2021).…”

Section: Resultsmentioning

confidence: 99%

“…These studies provide strong evidence supporting the importance of the NAD-synthesizing function of NMNAT2 in axonal health (Araki et al, 2004; Milde et al, 2013a; Yan et al, 2010). A sharp decline in axonal NAD levels together with the activation of Sarm1 (sterile alpha and TIR motif containing protein 1), a newly discovered NAD(P) glycohydrolase, were ascribed to axonal degeneration (Angeletti et al, 2022; Di Stefano et al, 2015; Gerdts et al, 2015). Global NMNAT2 knockout (KO) results in premature death at birth with a severe peripheral nerve defect and truncated axons in the optic nerve (Gilley et al, 2013a; Hicks et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

“…Despite being a member of the Myd88 immune adaptor protein family, SARM1 itself has no clear role in innate immunity. SARM1 catalyzes NAD + hydrolysis (Figley and DiAntonio, 2020; Gerdts et al, 2015; Gerdts et al, 2016; Jiang et al, 2020) and alternatively possesses transglycosidation (base exchange) activity (Angeletti et al, 2022). These enzymatic activities are all activated by an increase in the ratio of nicotinamide mononucleotide (NMN) to NAD + , even without axonal injuries (Figley et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

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NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

Niou

Yang

Sri

et al. 2022

Preprint

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Here we show that deleting NMNAT2 from cortical glutamatergic neurons (NMNAT2 cKO) results in progressive axonal loss, neuroinflammation, small hippocampi and enlarged ventricles. Interestingly, dramatic neuroinflammation responses were observed around the long-range axonal tracts of NMNAT2 cKO cortical neurons. In addition to the neurodegenerative-like phenotype, we also found the absence of whisker-representation patterns (barrels) in the primary somatosensory cortex of NMNAT2 cKO mice. These observations suggest that NMNAT2 is required in developing cortical circuits and in maintaining the health of cortical neurons. Unbiased transcriptomic analysis suggests that NMNAT2 loss in cortical neurons after axonal outgrowth phase upregulates mitochondria function while greatly reducing synaptogenesis pathways. Complete loss of Sarm1 function in NMNAT2 cKO mice restores barrel map formation and axonal integrity and abolishes the inflammatory response. Interestingly, reducing Sarm1 function in NMNAT2 cKO mice by deleting only one copy of Sarm1 restores barrel map formation but did not diminish the neurodegenerative-like phenotype. Only complete loss of Sarm1 prevents neurodegeneration and inflammatory responses.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

Niou

Yang

Sri

et al. 2022

Preprint

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“…One possible explanation for these findings is that degeneration of neuronal processes in this context could result from one of the additional enzyme activities of SARM1, which include NADP hydrolysis and cyclisation, and base exchange of nicotinamide of NAD(P) with other endogenous pyridine bases such as nicotinic acid (Zhao et al, 2019 ; Angeletti et al, 2021 ; Figley et al, 2021 ). These may lead to reduced ROS buffering capability due to lowering of NADPH, or to calcium mobilization due to generation of NaADP, the most potent known calcium mobilizing signal (Galione et al, 2000 ; Angeletti et al, 2021 ). Indeed, a circa 50% decline in NAD + , as observed here at 24 hpi, is not sufficient to kill axons or cells since doses of NAMPT inhibitor FK866 that depletes NAD + to or beyond this level, are not lethal (Di Stefano et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

“…SARM1 (Sterile alpha and armadillo motif-containing protein 1) has a well-established role in Wallerian degeneration and is regarded as a central executioner in this conserved axon degeneration pathway involving NAD-related metabolism. The SARM1 TIR domain has NAD + consuming glycohydrolase (NADase) activity, considered critical for its prodegenerative capacity (Essuman et al, 2017 ; Horsefield et al, 2019 ), although it has additional NADP hydrolase and base exchange activities that could also play important roles (Angeletti et al, 2021 ). As axons are often used by neurotropic viruses to enter neuronal and glial somas where the cellular machinery they use to replicate is located (Richards et al, 2021 ) it has been suggested that the known response of SARM1 to bunyavirus or rabies virus infection (both negative strand RNA viruses) could represent a mechanism to limit the spread of neurotropic virus (Mukherjee et al, 2013 ; Sundaramoorthy et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection

Crawford

Antoniou²,

Komarek

et al. 2022

Front. Mol. Neurosci.

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Zika virus (ZIKV) is a neurotropic flavivirus recently linked to congenital ZIKV syndrome in children and encephalitis and Guillain-Barré syndrome in adults. Neurotropic viruses often use axons to traffic to neuronal or glial cell somas where they either remain latent or replicate and proceed to infect new cells. Consequently, it has been suggested that axon degeneration could represent an evolutionarily conserved mechanism to limit viral spread. Whilst it is not known if ZIKV transits in axons, we previously reported that ZIKV infection of glial cells in a murine spinal cord-derived cell culture model of the CNS is associated with a profound loss of neuronal cell processes. This, despite that postmitotic neurons are relatively refractory to infection and death. Here, we tested the hypothesis that ZIKV-associated degeneration of neuronal processes is dependent on activation of Sterile alpha and armadillo motif-containing protein 1 (SARM1), an NADase that acts as a central executioner in a conserved axon degeneration pathway. To test this, we infected wild type and Sarm1 homozygous or heterozygous null cell cultures with ZIKV and examined NAD+ levels as well as the survival of neurons and their processes. Unexpectedly, ZIKV infection led to a rapid SARM1-independent reduction in NAD+. Nonetheless, the subsequent profound loss of neuronal cell processes was SARM1-dependent and was preceded by early changes in the appearance of β-tubulin III staining. Together, these data identify a role for SARM1 in the pathogenesis of ZIKV infection, which may reflect SARM1's conserved prodegenerative function, independent of its NADase activity.

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How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

Wenzl,

de Oliveira Mann

2024

FEBS Letters

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Cyclic nucleotides are the most diversified category of second messengers and are found in all organisms modulating diverse pathways. While cAMP and cGMP have been studied over 50 years, cyclic di‐nucleotide signaling in eukaryotes emerged only recently with the anti‐viral molecule 2´3´cGAMP. Recent breakthrough discoveries have revealed not only the astonishing chemical diversity of cyclic nucleotides but also surprisingly deep‐rooted evolutionary origins of cyclic oligo‐nucleotide signaling pathways and structural conservation of the proteins involved in their synthesis and signaling. Here we discuss how enzyme‐centered approaches have paved the way for the identification of several cyclic nucleotide signals, focusing on the advantages and challenges associated with deciphering the activation mechanisms of such enzymes.

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SARM1 is a multi-functional NAD(P)ase with prominent base exchange activity, all regulated bymultiple physiologically relevant NAD metabolites

Cited by 58 publications

References 79 publications

NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

SARM1 Depletion Slows Axon Degeneration in a CNS Model of Neurotropic Viral Infection

How enzyme‐centered approaches are advancing research on cyclic oligo‐nucleotides

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