Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed

Izadifar, Azadeh; Courchet, Julien; Virga, Daniel M.; Verreet, Tine; Hamilton, Stevie; Ayaz, Derya; Misbaer, Anke; Vandenbogaerde, Sofie; Monteiro, Laloé; Petrović, M.M.; Sachse, Sonja; Yan, Bing; Erfurth, Maria-Luise; Dascenco, Dan; Kise, Yoshiaki; Yan, Jiekun; Edwards-Faret, Gabriela; Lewis, Tommy L.; Polleux, Franck; Schmucker, Dietmar

doi:10.1016/j.neuron.2021.07.006

Cited by 28 publications

(27 citation statements)

References 81 publications

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“…However, this appears to be consistent with a previous report showing that overexpression of (WT) SARM1 suppresses de novo synthesis of exogenous proteins in an NADasedependent manner (Izadifar et al, 2021). In support of this mechanism, we found that the cell permeable NAD + precursor nicotinamde riboside (NR) allows higher levels of expression of both zsGreen and the putative strong NADase GoF SARM1 variants themselves, presumably by boosting NAD + synthesis and thus delaying the point at which NAD + becomes limiting for de novo protein synthesis as a result of enhanced SARM1 NADase activity (Figure 2 -figure supplement 2B and 2C).…”

Section: Several Als Patient-specific Sarm1 Arm Domain Coding Variants In Project Mine Df1 Increase Nad + Depletion In Transfected Hek 29supporting

confidence: 93%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

eLife

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SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

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Section: Several Als Patient-specific Sarm1 Arm Domain Coding Variants In Project Mine Df1 Increase Nad + Depletion In Transfected Hek 29supporting

confidence: 93%

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Gilley

Jackson

Pipis

et al. 2021

eLife

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“…Future studies will be required to address these alternative but not mutually exclusive hypothetical mechanisms for the regulation of the axonal levels of cortactin and drebrin by SARM1 KO. Consistent with the possible role of SARM1 as a negative regulator of axonal translation, Izadifar et al (2021) recently reported that SARM1 may impede the synthesis of axon-protective proteins such as Nmnat.…”

Section: Discussionmentioning

confidence: 61%

“…Also, whether SARM1 KO will affect the branching morphogenesis of neuronal populations other than sensory neurons remains to be determined. However, a generalized role of SARM1 in negative regulation of axon morphology is suggested by the recent demonstration of a role of SARM1 in branching of mechanosensory neurons in Drosophila ( Izadifar et al, 2021 ). The data presented herein provide a link between SARM1 and the suppression of the dynamics of both the axonal actin filament and microtubule cytoskeletons.…”

Section: Discussionmentioning

confidence: 99%

SARM1 Suppresses Axon Branching Through Attenuation of Axonal Cytoskeletal Dynamics

Ketschek

Holland

Gallo

2022

Front. Mol. Neurosci.

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Axon branching is a fundamental aspect of neuronal morphogenesis, neuronal circuit formation, and response of the nervous system to injury. Sterile alpha and TIR motif containing 1 (SARM1) was initially identified as promoting Wallerian degeneration of axons. We now report a novel function of SARM1 in postnatal sensory neurons; the suppression of axon branching. Axon collateral branches develop from axonal filopodia precursors through the coordination of the actin and microtubule cytoskeleton. In vitro analysis revealed that cultured P0-2 dorsal root ganglion sensory neurons from a SARM1 knockout (KO) mouse exhibit increased numbers of collateral branches and axonal filopodia relative to wild-type neurons. In SARM1 KO mice, cutaneous sensory endings exhibit increased branching in the skin in vivo with normal density of innervation. Transient axonal actin patches serve as cytoskeletal platforms from which axonal filopodia emerge. Live imaging analysis of axonal actin dynamics showed that SARM1 KO neurons exhibit increased rates of axonal actin patch formation and increased probability that individual patches will give rise to a filopodium before dissipating. SARM1 KO axons contain elevated levels of drebrin and cortactin, two actin regulatory proteins that are positive regulators of actin patches, filopodia formation, and branching. Live imaging of microtubule plus tip dynamics revealed an increase in the rate of formation and velocity of polymerizing tips along the axons of SARM1 KO neurons. Stationary mitochondria define sites along the axon where branches may arise, and the axons of SARM1 KO sensory neurons exhibit an increase in stationary mitochondria. These data reveal SARM1 to be a negative regulator of axonal cytoskeletal dynamics and collateral branching.

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“…The discovery of NMNAT2’s role in axonal health ( 21, 62 ) provides a critical entry point into understanding how neuronal function is actively maintained. Here, we reveal mechanistic insights into the NAD synthesis activity of NMNAT2 that enables on-board glycolysis to generate the ATP necessary to fuel fast axonal transport of vesicular cargos.…”

Section: Discussionmentioning

confidence: 99%

NAD homeostasis maintained by NMNAT2 supports vesicular glycolysis and fuels fast axonal transport in distal axons of cortical glutamatergic neurons in mice

Yang

Niou

Enriquez

et al. 2022

Preprint

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Axonal transport, an ATP demanding process, plays a critical role in maintaining axonal and neuronal health. ATP in neurons is synthesized by glycolysis and mitochondrial respiration, both driven by proper NAD+/NADH redox potentials. NMNAT2 is the major neuronal NAD+ synthesizing enzyme and is a key axonal maintenance factor. Here, we show that NMNAT2 co-migrates with fast vesicular cargos in axons and is required for fast axonal transport in the distal axons of cortical neurons. Using SoNar sensor imaging to detect axonal NAD+ and NADH, we show that NMNAT2 is critical in maintaining NAD+/NADH potentials in distal axons. With Syn-ATP sensor imaging to detect synaptic vesicle ATP levels (sv-ATP), we demonstrate that glycolysis is the major provider of sv-ATP and NMNAT2 deletion significantly reduces sv-ATP levels. NAD+ supplementation to NMNAT2 KO neurons restores sv-ATP levels and fast axonal transports in a glycolysis-dependent manner. Together, these data show that NMNAT2 maintains the local NAD+/NADH redox potential and sustains on-board glycolysis to meet the bioenergetic demands of fast vesicular transport in distal axons. Intriguingly, mitochondrial respiration contributes significantly to sv-ATP levels in NMNAT2 KO axons. This finding suggests that NMNAT2 deletion induces metabolic plasticity by engaging mitochondria. Surprisingly, supplying NMN, the substrate for NMNAT2 in NAD+ synthesis, restores sv-ATP and axonal transport in NMNAT2 KO axons with an efficacy similar to NAD+. The restoration of NMNAT2 KO distal axonal sv-ATP levels and vesicle transport by NMN requires mitochondrial respiration, while the rescue by NAD+ is independent of mitochondrial respiration. Based on these findings, we hypothesize that NMN rescues glycolysis to restore axonal transport in NMNAT2 KO axons by taking advantage of the compensatory ATP-generating metabolic pathways triggered by NMNAT2 loss.

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Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed

Cited by 28 publications

References 81 publications

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

SARM1 Suppresses Axon Branching Through Attenuation of Axonal Cytoskeletal Dynamics

NAD homeostasis maintained by NMNAT2 supports vesicular glycolysis and fuels fast axonal transport in distal axons of cortical glutamatergic neurons in mice

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