A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death

Zhao, Zhuo; Xie, Xu Jie; Li, Wan Hua; Liu, Jun; Chen, Zhe; Zhang, Ben; Li, Ting; Li, Song Lu; Lu, Jun Gang; Zhang, Liangren; Xu, Zhengshuang; Lee, Hon Cheung; Zhao, Yong

doi:10.1016/j.isci.2019.05.001

Cited by 153 publications

(284 citation statements)

References 68 publications

Supporting

Mentioning

256

Contrasting

Order By: Relevance

“…We next sought to determine the molecular mechanisms required for retinal degeneration in the NMNAT1-deficient retina. The loss of NMNAT2 induces an increase in NMN that is hypothesized to activate SARM1-dependent axon degeneration 53,54 . Our metabolomic analysis revealed that NMN is increased in the NMNAT1-deficient retinas ( Figure 1D), and previous studies have detected SARM1 in mouse and bovine photoreceptor cells [55][56][57] .…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

“…NMNAT enzymes inhibit the activation of SARM1 30 , potentially by consuming the NAD + precursor NMN, which is postulated to activate SARM1 53,54 . Prior to our study, loss of NMNAT2 was the only known trigger of SARM1 activation.…”

Section: Discussionmentioning

confidence: 99%

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Sasaki

Kakita

Kubota

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…SAM domains that mediate constitutive homomultimerization, and an executioner TIR domain (12). Upon injury, N-terminal inhibition is relieved, potentially via a rise in nicotinamide mononucleotide (NMN) secondary to NMN adenylyltransferase 2 (NMNAT2) loss (13)(14)(15), which thereby activates the intrinsic SARM1 TIR NADase (12,16). Active SARM1 cleaves the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), generating nicotinamide and the calcium-mobilizing agents ADPR and cADPR (16), leading to local NAD + depletion, followed by metabolic collapse and axon fragmentation (17).…”

Section: Introductionmentioning

confidence: 99%

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

et al. 2019

View full text Add to dashboard Cite

“…Its activation triggered axon degeneration locally and induced NAD depletion (89), suggesting that it may have NAD-hydrolyzing activity. Consistently, the Toll/interleukin-1 receptor (TIR) domain of SARM1, recombinantly produced and purified, was shown to be an effective NADase (87,88). Surprisingly, analysis of its hydrolysis products by HPLC showed, in addition to ADP-ribose, a small peak corresponding to cADPR (87, 88).…”

Section: A New Enzyme Emergesmentioning

confidence: 98%

“…It is thus surprising that sterile ␣ and Toll/interleukin-1 receptor motif-containing 1 (SARM1), a protein unrelated to and having no sequence similarity with CD38, has recently been shown to be able to catalyze the synthesis of cADPR (87,88). This unexpected discovery is a convergence of two different and independent lines of investigation.…”

Section: A New Enzyme Emergesmentioning

confidence: 99%

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Lee

Zhao

2019

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

Edited by Mike Shipston Cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP) are two structurally distinct messengers that mobilize the endoplasmic and endolysosomal Ca 2؉ stores, respectively. Both are synthesized by the CD38 molecule (CD38), which has long been thought to be a type II membrane protein whose catalytic domain, intriguingly, faces to the outside of the cell. Accordingly, for more than 20 years, it has remained unresolved how CD38 can use cytosolic substrates such as NAD and NADP to produce messengers that target intracellular Ca 2؉ stores. The discovery of type III CD38, whose catalytic domain faces the cytosol, has now begun to clarify this topological conundrum. This article reviews the ideas and clues leading to the discovery of the type III CD38; highlights an innovative approach for uncovering its natural existence; and discusses the regulators of its activity, folding, and degradation. We also review the compartmentalization of cADPR and NAADP biogenesis. We further discuss the possible mechanisms that promote type III CD38 expression and appraise a proposal of a Ca 2؉-signaling mechanism based on substrate limitation and product translocation. The surprising finding of another enzyme that produces cADPR and NAADP, sterile ␣ and TIR motif-containing 1 (SARM1), is described. SARM1 regulates axonal degeneration and has no sequence similarity with CD38 but can catalyze the same set of multireactions and has the same cytosolic orientation as the type III CD38. The intriguing finding that SARM1 is activated by nicotinamide mononucleotide to produce cADPR and NAADP suggests that it may function as a regulated Ca 2؉-signaling enzyme like CD38.

show abstract

A Cell-Permeant Mimetic of NMN Activates SARM1 to Produce Cyclic ADP-Ribose and Induce Non-apoptotic Cell Death

Cited by 153 publications

References 68 publications

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

SARM1 depletion rescues NMNAT1 dependent photoreceptor cell death and retinal degeneration

Vincristine and bortezomib use distinct upstream mechanisms to activate a common SARM1-dependent axon degeneration program

Resolving the topological enigma in Ca2+ signaling by cyclic ADP-ribose and NAADP

Contact Info

Product

Resources

About