cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons

Sasaki, Yo; Engber, Thomas M.; Hughes, Robert; Figley, Matthew D.; Wu, Tong; Bosanac, Todd; Devraj, Rajesh; Milbrandt, Jeffrey; Krauss, Raul; DiAntonio, Aaron

doi:10.1016/j.expneurol.2020.113252

Cited by 85 publications

(137 citation statements)

References 48 publications

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“…Nmnat1 was excised in these mice via tamoxifen administration at 2 months of age (NMNAT1 cKO: SARM1 KO). First, we assessed SARM1 activation via measurement of cADPR, a product of the SARM1 NAD + cleavage enzyme and a biomarker of SARM1 activity as well as NAD + ( Sasaki et al, 2020 ). While the loss of NAD + was not statistically significant at 25 days post tamoxifen injection in NMNAT1 cKO retina ( Figure 1A ), there was significant loss of NAD + at 29 to 32 days post tamoxifen in NMNAT1 cKO but not in NMNAT1 cKO: SARM1 KO retina ( Figure 4A ).…”

Section: Resultsmentioning

confidence: 99%

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: Resultsmentioning

confidence: 99%

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

Sasaki

Kakita

Kubota

et al. 2020

eLife

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“…We recently reported that cADPR is a biomarker of SARM1 activity 39 . After neuronal injury, SARM1 is activated and intracellular cADPR is increased in a SARM1 dependent manner 39 .…”

Section: Resultsmentioning

confidence: 99%

“…We recently reported that cADPR is a biomarker of SARM1 activity 39 . After neuronal injury, SARM1 is activated and intracellular cADPR is increased in a SARM1 dependent manner 39 . We observed a significant increase in cADPR in NMNAT1 cKO and this increase was completely blocked in the NMNAT1 cKO:SARM1 KO retina ( Figure 7H).…”

Section: Resultsmentioning

confidence: 99%

“…Finally, we determined the mechanism by which loss of NMNAT1 leads to photoreceptor degeneration. Loss of NMNAT1 leads to activation of SARM1 in photoreceptors, much as loss of NMNAT2 leads to SARM1 activation in axons 39 . Moreover, photoreceptor degeneration is mediated by SARM1 in the absence of NMNAT1, much as axon degeneration and perinatal lethality is mediated by SARM1 in the absence of NMNAT2 28,31 .…”

Section: Nmnat1 Plays Important Roles In Diverse Retinal Functions Omentioning

confidence: 99%

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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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“…Importantly, this nding is not in con ict with reports that NMNAT/NAD + depletion is involved in catastrophic degeneration [45]. Studies in mouse dorsal root ganglion (DRG) neuron cultures have shown that there is slow NAD + decline for roughly 2 hours after transection likely owing to NMNAT2 degradation, followed by a fast SARM1-dependent NAD + degradation [44,45,48]. To explain the different phenotypes of Sarm1 −/− and Wld s with respect to spheroid formation after injury, we propose a working model by which SARM1 is inactive during the latent phase and then becomes active after spheroidal rupture to accelerate NAD + depletion during the catastrophic phase of axon degeneration.…”

Section: Discussionmentioning

confidence: 48%

Regulation of degenerative spheroids after injury

Yan

Gamage

Cushman

et al. 2020

Preprint

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Background Neuronal injury leads to rapid, programmed disintegration of axons distal to the site of lesion. Much like other forms of axon degeneration ( e.g. developmental pruning, toxic insult from neurodegenerative disorder), Wallerian degeneration associated with injury is preceded by spheroid formation along axons. The mechanisms by which injury leads to formation of spheroids remains elusive. Methods Here, using wild-type and mutant neonatal mouse primary sympathetic neurons, immunostaining and calcium imaging, we investigate the roles of players previously implicated in the progression of Wallerian degeneration in injury-induced spheroid formation. Results We find that intra-axonal calcium flux is accompanied by actin-Rho dependent growth of calcium rich axonal spheroids that eventually rupture, releasing material to the extracellular space prior to catastrophic axon degeneration. Importantly, after injury, Sarm1 -/- and DR6 -/- , but not Wld s (excess NAD + ) neurons, are capable of forming spheroids that eventually rupture, releasing their contents to the extracellular space. Supplementation of exogenous NAD + or expressing WLD s suppresses Rho-dependent spheroid formation and degeneration in response to injury. Conclusions Taken together, our findings place Rho-actin and NAD + upstream of spheroid formation and may suggest that other mediators of degeneration, such as DR6 and SARM1, mediate post-spheroid rupture events that lead to catastrophic axon disassembly.

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cADPR is a gene dosage-sensitive biomarker of SARM1 activity in healthy, compromised, and degenerating axons

Cited by 85 publications

References 48 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

Regulation of degenerative spheroids after injury

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