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dc.contributor.authorSasaki, Y
dc.contributor.authorZhu, J
dc.contributor.authorShi, Y
dc.contributor.authorGu, W
dc.contributor.authorKobe, B
dc.contributor.authorVe, T
dc.contributor.authorDiAntonio, A
dc.contributor.authorMilbrandt, J
dc.date.accessioned2021-09-01T04:34:37Z
dc.date.available2021-09-01T04:34:37Z
dc.date.issued2021
dc.identifier.issn0014-4886
dc.identifier.doi10.1016/j.expneurol.2021.113842
dc.identifier.urihttp://hdl.handle.net/10072/407468
dc.description.abstractSARM1 is an inducible NAD+ hydrolase that is the central executioner of pathological axon loss. Recently, we elucidated the molecular mechanism of SARM1 activation, demonstrating that SARM1 is a metabolic sensor regulated by the levels of NAD+ and its precursor, nicotinamide mononucleotide (NMN), via their competitive binding to an allosteric site within the SARM1 N-terminal ARM domain. In healthy neurons with abundant NAD+, binding of NAD+ blocks access of NMN to this allosteric site. However, with injury or disease the levels of the NAD+ biosynthetic enzyme NMNAT2 drop, increasing the NMN/ NAD+ ratio and thereby promoting NMN binding to the SARM1 allosteric site, which in turn induces a conformational change activating the SARM1 NAD+ hydrolase. Hence, NAD+ metabolites both regulate the activation of SARM1 and, in turn, are regulated by the SARM1 NAD+ hydrolase. This dual upstream and downstream role for NAD+ metabolites in SARM1 function has hindered mechanistic understanding of axoprotective mechanisms that manipulate the NAD+ metabolome. Here we reevaluate two methods that potently block axon degeneration via modulation of NAD+ related metabolites, 1) the administration of the NMN biosynthesis inhibitor FK866 in conjunction with the NAD+ precursor nicotinic acid riboside (NaR) and 2) the neuronal expression of the bacterial enzyme NMN deamidase. We find that these approaches not only lead to a decrease in the levels of the SARM1 activator NMN, but also an increase in the levels of the NAD+ precursor nicotinic acid mononucleotide (NaMN). We show that NaMN inhibits SARM1 activation, and demonstrate that this NaMN-mediated inhibition is important for the long-term axon protection induced by these treatments. Analysis of the NaMN-ARM domain co-crystal structure shows that NaMN competes with NMN for binding to the SARM1 allosteric site and promotes the open, autoinhibited configuration of SARM1 ARM domain. Together, these results demonstrate that the SARM1 allosteric pocket can bind a diverse set of metabolites including NMN, NAD+, and NaMN to monitor cellular NAD+ homeostasis and regulate SARM1 NAD+ hydrolase activity. The relative promiscuity of the allosteric site may enable the development of potent pharmacological inhibitors of SARM1 activation for the treatment of neurodegenerative disorders.
dc.description.peerreviewedYes
dc.languageeng
dc.publisherElsevier BV
dc.relation.ispartofpagefrom113842
dc.relation.ispartofjournalExperimental Neurology
dc.relation.ispartofvolume345
dc.subject.fieldofresearchClinical sciences
dc.subject.fieldofresearchcode3202
dc.subject.keywordsNADase
dc.subject.keywordsNAMPT
dc.subject.keywordsNMR
dc.subject.keywordsNeuropathy
dc.subject.keywordsTIR
dc.titleNicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection
dc.typeJournal article
dc.type.descriptionC1 - Articles
dcterms.bibliographicCitationSasaki, Y; Zhu, J; Shi, Y; Gu, W; Kobe, B; Ve, T; DiAntonio, A; Milbrandt, J, Nicotinic acid mononucleotide is an allosteric SARM1 inhibitor promoting axonal protection, Experimental Neurology, 2021, 345, pp. 113842
dcterms.dateAccepted2021-08-12
dcterms.licensehttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.date.updated2021-09-01T04:26:48Z
dc.description.versionAccepted Manuscript (AM)
gro.rights.copyright© 2021 Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International Licence (http://creativecommons.org/licenses/by-nc-nd/4.0/) which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
gro.hasfulltextFull Text
gro.griffith.authorShi, Yun
gro.griffith.authorVe, Thomas


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