The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease

Figley, Matthew D.; DiAntonio, Aaron

doi:10.1016/j.conb.2020.02.012

Cited by 105 publications

(98 citation statements)

References 76 publications

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“…Loss of NMNAT1 in photoreceptors or NMNAT2 in axons leads to the SARM1-induced death of photoreceptors or axons, respectively. This surprising result extends our understanding of both the mechanisms causing retinal degeneration and the potential role of SARM1 in human disease ( Figley and DiAntonio, 2020 ; Coleman and Höke, 2020 ).…”

Section: Discussionsupporting

confidence: 68%

“…When NMNAT1 is present in the axon, it can compensate for the injury-induced rapid loss of NMNAT2, the endogenous axonal NMNAT ( Gilley and Coleman, 2010 ). NMNAT2 in turn, inhibits SARM1, an inducible NAD + cleavage enzyme (NADase) that is the central executioner of axon degeneration ( Gilley and Coleman, 2010 ; Gerdts et al, 2015 ; Sasaki et al, 2016 ; Gilley et al, 2015 ; Figley and DiAntonio, 2020 ). Hence, mutations in NMNAT1 may promote retinal degeneration through the direct impact on NAD + biosynthesis and/or through the regulation of the SARM1-dependent degenerative program.…”

Section: Introductionmentioning

confidence: 99%

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SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

eLife

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Leber congenital amaurosis type nine is an autosomal recessive retinopathy caused by mutations of the NAD+ synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1, patients do not manifest pathologies other than retinal degeneration. Here we demonstrate that widespread NMNAT1 depletion in adult mice mirrors the human pathology, with selective loss of photoreceptors highlighting the exquisite vulnerability of these cells to NMNAT1 loss. Conditional deletion demonstrates that NMNAT1 is required within the photoreceptor. Mechanistically, loss of NMNAT1 activates the NADase SARM1, the central executioner of axon degeneration, to trigger photoreceptor death and vision loss. Hence, the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, highlighting an unexpected shared mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway and identifies SARM1 as a therapeutic candidate for retinopathies.

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Section: Discussionsupporting

confidence: 68%

Section: Introductionmentioning

confidence: 99%

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

eLife

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“…When NMNAT1 is present in the axon, it can compensate for the injury-induced rapid loss of NMNAT2, the endogenous axonal NMNAT 28 . NMNAT2 in turn, inhibits SARM1, an inducible NAD + cleavage enzyme (NADase) that is the central executioner of axon degeneration [28][29][30][31][32] . Hence, mutations in NMNAT1 may promote retinal degeneration through the direct impact on NAD + biosynthesis and/or through the regulation of the SARM1-dependent degenerative program.…”

Section: Nmnat1 Plays Important Roles In Diverse Retinal Functions Omentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

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Leber congenital amaurosis type 9 (LCA9) is an autosomal recessive, early onset retinal neurodegenerative disease caused by mutations in the gene encoding the nuclear NAD + synthesis enzyme NMNAT1. Despite the ubiquitous expression of NMNAT1 and its role in NAD + homeostasis, LCA9 patients do not manifest pathologies other than retinal degeneration.To investigate the mechanism of degeneration, we examined retinas of developing and adult mice with conditional or tissue-specific NMNAT1 loss. Widespread NMNAT1 depletion in adult mice resulted in loss of photoreceptors, indicating these cells are exquisitely vulnerable to NMNAT1 loss. NMNAT1 is required within the photoreceptor, as conditional deletion of NMNAT1 in photoreceptors but not retinal pigment epithelial cells is sufficient to cause photoreceptor neurodegeneration and vision loss. Moreover, delivery of NMNAT1 into eyes of adult mice lacking NMNAT1 using a modified AAV8 vector containing a photoreceptor-specific promoter rescued the retinal degeneration phenotype and partially restored vision. Finally, we defined the molecular mechanism driving photoreceptor cell death. Loss of NMNAT1 activates SARM1, an inducible NADase best known as the central executioner of axon degeneration. SARM1 is required for the photoreceptor death and vision loss that occurs following NMNAT1 deletion. This surprising finding demonstrates that the essential function of NMNAT1 in photoreceptors is to inhibit SARM1, and establishes a commonality of mechanism between axonal degeneration and photoreceptor neurodegeneration. These results define a novel SARM1-dependent photoreceptor cell death pathway that is active in the setting of dysregulated NAD + metabolism and identifies SARM1 as a therapeutic candidate for the treatment of retinal degeneration.

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“…The combined effect of increased Nmnat1 and decreased activation of SARM1 leads to a great increase in axonal nicotinamide adenine dinucleotide, which may itself prevent axon degeneration through ATP synthesis [75]. Alternatively, other SARM1 substrates or its calcium mobilizing products could be important for the later stages of Wallerian axon degeneration [76][77][78][79]. While this and other aspects are under investigation, this study proposes a mechanism by which obestatin preserves axonal integrity by the activation of mitochondrial-mediated axonal transport of calpastatin and the inhibition of pro-degenerative molecule SARM1.…”

Section: Discussionmentioning

confidence: 99%

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

Camiña¹,

Sánchez‐Temprano²,

Leal‐López³

et al. 2020

Preprint

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Background. Injuries to the peripheral nerve system are common conditions, with broad spectrum of symptoms depending on the impaired nerves and severity of damage. Although peripheral nervous system retains a remarkable ability for regeneration, it is estimated that less than ten percent of patients fully recover function after nerve injury and the available treatments remain suboptimal. Here, we identify a role for the obestatin/GPR39 system in the regulation of the Schwann cell plasticity as well as in the preservation of neuromuscular synapses in the course of nerve repair. Methods. Utilizing a compression model of sciatic nerve injury, axonotmesis, we assessed the obestatin-related regenerative response in the peripheral nerve system. The role of the obestatin/GPR39 system was further evaluated on immortalized rat Schwann cells, IFRS1, and the model of neuronal differentiation, PC12 cells. The interactions between SCs and neurons was evaluated using a co-culture system that combine the SC cell line IFRS1 and the NGF-primed PC12. Results. Obestatin signaling directs proliferation and migration of Schwann cells that sustain axonal regrowth and later remyelinate regenerated axons. We provide evidence supporting the preservation of skeletal muscle by the maintenance of neuromuscular synapses through the axonal regulation of calpain-calpastatin proteolytic system. This encompasses the control of skeletal muscle homeostasis by regulation of the ubiquitin proteasome system and the autophagy machinery. Conclusions. These results provide important insights into how the obestatin/GPR39 system promotes nerve repair through integration of multiple molecular cues of neuron-Schwann cells crosstalk aimed to promote axon growth and guide axons back to their targets.

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The SARM1 axon degeneration pathway: control of the NAD+ metabolome regulates axon survival in health and disease

Cited by 105 publications

References 76 publications

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1-dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Obestatin signaling controls Schwann cells and axonal transport to counteract neuromuscular synaptic loss in skeletal muscle

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