SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration

Figley, Matthew D.; Gu, Weixi; Nanson, J.D.; Shi, Yun; Sasaki, Yo; Cunnea, Katie; Malde, Alpeshkumar K.; Jia, Xinying; Luo, Zhenyao; Saikot, Forhad Karim; Mosaiab, Tamim; Masic, Veronika; Holt, Stephanie; Hartley-Tassell, Lauren E.; McGuinness, Helen Y.; Manik, M.K.; Bosanac, Todd; Landsberg, Michael J.; Kerry, Philip S.; Mobli, Mehdi; Hughes, Robert; Milbrandt, Jeffrey; Kobe, Boštjan; DiAntonio, Aaron; Ve, Thomas

doi:10.1016/j.neuron.2021.02.009

Cited by 185 publications

(284 citation statements)

References 110 publications

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“…However, recent studies suggest that NAD itself is an inhibitor of SARM1 activation and the balance between NMN and NAD controls the activation of SARM1 (Figley et al, 2021, Jiang et al, 2020a.…”

Section: Introductionmentioning

confidence: 99%

“…It is self-inhibitory and is activated by nicotinamide mononucleotide (NMN) ( Zhao et al, 2019 ), resulting in depletion of the intracellular NAD-pool ( Essuman et al, 2017 ; Zhao et al, 2019 ). However, recent studies suggest that nicotinamide adenine dinucleotide (NAD) itself is an inhibitor of SARM1 activation and the balance between NMN and NAD controls the activation of SARM1 ( Figley et al, 2021 ; Jiang et al, 2020 ; Sporny et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Huang

Cai

et al. 2021

eLife

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SARM1 regulates axonal degeneration through its NAD-metabolizing activity and is a drug target for neurodegenerative disorders. We designed and synthesized fluorescent conjugates of styryl derivative with pyridine to serve as substrates of SARM1, which exhibited large red-shifts after conversion. With the conjugates, SARM1 activation was visualized in live cells following elevation of endogenous NMN or treatment with a cell-permeant NMN-analog. In neurons, imaging documented mouse SARM1 activation preceded vincristine-induced axonal degeneration by hours. Library screening identified a derivative of nisoldipine as a covalent inhibitor of SARM1 that reacted with the cysteines, especially Cys311 in its ARM domain and blocked its NMN-activation, protecting axons from degeneration. The Cryo-EM structure showed that SARM1 was locked into an inactive conformation by the inhibitor, uncovering a potential neuroprotective mechanism of dihydropyridines.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Huang

Cai

et al. 2021

eLife

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“…Mitochondrial stress, trauma or other insults lead to loss of nicotinamide mononucleotide adenylyl-transferase 2 (NMNAT2), an NAD-synthesizing enzyme, in axons that depletes NAD+ and raises the level of its precursor nicotinamide mononucleotide (NMN) [20, 47]. Low NAD+ and high NMN levels regulate release of auto-inhibition of SARM1 NADase activity, which further depletes NAD+ and axon energy stores [11, 21, 38, 73, 76]. Axons with swollen mitochondria were significantly increased at 3 days after TBI in Sarm1 WT and Sarm1 KO mice [51].…”

Section: Discussionmentioning

confidence: 99%

“…After injury or mitochondrial dysfunction, the SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) protein executes a highly conserved molecular axon death pathway [26, 47, 67, 80]. Injury releases SARM1 from an auto-inhibited state that is found in healthy axons [21, 73, 76]. Active SARM1 is a glycohydrolase which depletes nicotinamide adenine dinucleotide (NAD+) that is critical for energy stores in axons [17, 22, 25].…”

Section: Introductionmentioning

confidence: 99%

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

Bradshaw

Knutsen

Korotcov

et al. 2021

Preprint

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Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. The Sarm1 gene is a central driver of axon degeneration through a conserved molecular pathway. Sarm1-/- mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of Sarm1 inactivation as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Using electron microscopy to quantify individual axons demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. MRI in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, TBI resulted in late-stage motor learning and sleep deficits that were ameliorated in Sarm1 KO mice. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.

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“…After injury or mitochondrial dysfunction, the SARM1 (sterile alpha and Toll/interleukin-1 receptor motif-containing 1) protein executes a highly conserved molecular axon degeneration pathway [ 27 , 48 , 70 , 84 ]. Injury releases SARM1 from an auto-inhibited state that is found in healthy axons [ 22 , 76 , 80 ]. Active SARM1 is a glycohydrolase which depletes nicotinamide adenine dinucleotide (NAD +) that is critical for energy stores in axons [ 18 , 23 , 26 ].…”

Section: Introductionmentioning

confidence: 99%

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

Bradshaw

Knutsen

Korotcov

et al. 2021

acta neuropathol commun

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Traumatic brain injury (TBI) causes chronic symptoms and increased risk of neurodegeneration. Axons in white matter tracts, such as the corpus callosum (CC), are critical components of neural circuits and particularly vulnerable to TBI. Treatments are needed to protect axons from traumatic injury and mitigate post-traumatic neurodegeneration. SARM1 protein is a central driver of axon degeneration through a conserved molecular pathway. Sarm1−/− mice with knockout (KO) of the Sarm1 gene enable genetic proof-of-concept testing of the SARM1 pathway as a therapeutic target. We evaluated Sarm1 deletion effects after TBI using a concussive model that causes traumatic axonal injury and progresses to CC atrophy at 10 weeks, indicating post-traumatic neurodegeneration. Sarm1 wild-type (WT) mice developed significant CC atrophy that was reduced in Sarm1 KO mice. Ultrastructural classification of pathology of individual axons, using electron microscopy, demonstrated that Sarm1 KO preserved more intact axons and reduced damaged or demyelinated axons. Longitudinal MRI studies in live mice identified significantly reduced CC volume after TBI in Sarm1 WT mice that was attenuated in Sarm1 KO mice. MR diffusion tensor imaging detected reduced fractional anisotropy in both genotypes while axial diffusivity remained higher in Sarm1 KO mice. Immunohistochemistry revealed significant attenuation of CC atrophy, myelin loss, and neuroinflammation in Sarm1 KO mice after TBI. Functionally, Sarm1 KO mice exhibited beneficial effects in motor learning and sleep behavior. Based on these findings, Sarm1 inactivation can protect axons and white matter tracts to improve translational outcomes associated with CC atrophy and post-traumatic neurodegeneration.

show abstract

SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration

Cited by 185 publications

References 110 publications

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Permeant fluorescent probes visualize the activation of SARM1 and uncover an anti-neurodegenerative drug candidate

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

Genetic inactivation of SARM1 axon degeneration pathway improves outcome trajectory after experimental traumatic brain injury based on pathological, radiological, and functional measures

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