Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1

Bratkowski, Matthew; Xie, Tian; Thayer, Desiree A.; Lad, Shradha; Mathur, Prakhyat; Yang, Y.; Danko, Gregory; Burdett, Thomas C.; Danao, Jean; Cantor, Aaron J.; Kozak, Jennifer A.; Brown, Sean P.; Bai, Xiao Chen; Sambashivan, Shilpa

doi:10.1016/j.celrep.2020.107999

Cited by 98 publications

(131 citation statements)

References 42 publications

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“…These different and extra interactions VMN forms could explain why VMN induces SARM1 activation more efficiently, compared to NMN. The compaction seen in both NMN and VMN-bound dSARM1 ARM structures likely represents the conformation of the ARM domain in active SARM1, based on the comparison with the more open cryo-EM (electron microscopy) structures of ligand-free and NAD-bound hSARM1, representing the inactive state of the protein (Bratkowski et al, 2020; Figley et al, 2021; Sporny et al, 2020) (Fig. 4F).…”

Section: Resultsmentioning

confidence: 99%

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

Loreto

Angeletti

Gilley

et al. 2020

Preprint

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SARM1 is intensively studied for its role in promoting axon degeneration in injury and disease. We identify VMN, a metabolite of the neurotoxin vacor, as a potent SARM1 activator, an action likely to underlie vacor neurotoxicity in humans. This study provides novel tools to study SARM1 regulation, supports drug discovery, further links programmed axon death to human disease and identifies a new model where axons are permanently rescued.

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Section: Resultsmentioning

confidence: 99%

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

Loreto

Angeletti

Gilley

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…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) [ 21 , 48 ]. Low NAD + and high NMN levels regulate release of auto-inhibition of SARM1 NADase activity, which further depletes NAD + and axon energy stores [ 12 , 22 , 39 , 76 , 80 ]. Axons with swollen mitochondria were significantly increased at 3 days after TBI in Sarm1 WT and Sarm1 KO mice [ 52 ].…”

Section: Discussionmentioning

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.

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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%

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

View full text Add to dashboard Cite

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.

show abstract

Structural and Mechanistic Regulation of the Pro-degenerative NAD Hydrolase SARM1

Cited by 98 publications

References 42 publications

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

Potent activation of SARM1 by NMN analogue VMN underlies vacor neurotoxicity

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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