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  • SARM1 is a metabolic sensor activated by an increased NMN/NAD+ ratio to trigger axon degeneration

    Author(s)
    Figley, Matthew D
    Gu, Weixi
    Nanson, Jeffrey D
    Shi, Yun
    Sasaki, Yo
    Cunnea, Katie
    Malde, Alpeshkumar K
    Jia, Xinying
    Luo, Zhenyao
    Saikot, Forhad K
    Mosaiab, Tamim
    Masic, Veronika
    Holt, Stephanie
    Hartley-Tassell, Lauren
    McGuinness, Helen Y
    Manik, Mohammad K
    Bosanac, Todd
    Landsberg, Michael J
    Kerry, Philip S
    Mobli, Mehdi
    Hughes, Robert O
    Milbrandt, Jeffrey
    Kobe, Bostjan
    DiAntonio, Aaron
    Ve, Thomas
    Griffith University Author(s)
    Malde, Alpesh K.
    Ve, Thomas
    Shi, Yun
    Mosaiab, Tamim
    Masic, Veronika
    Holt, Stephanie J.
    Hartley-Tassell, Lauren E.
    Year published
    2021
    Metadata
    Show full item record
    Abstract
    Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD +)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD +, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD + and show that both metabolites compete for binding to the auto-inhibitory ...
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    Axon degeneration is a central pathological feature of many neurodegenerative diseases. Sterile alpha and Toll/interleukin-1 receptor motif-containing 1 (SARM1) is a nicotinamide adenine dinucleotide (NAD +)-cleaving enzyme whose activation triggers axon destruction. Loss of the biosynthetic enzyme NMNAT2, which converts nicotinamide mononucleotide (NMN) to NAD +, activates SARM1 via an unknown mechanism. Using structural, biochemical, biophysical, and cellular assays, we demonstrate that SARM1 is activated by an increase in the ratio of NMN to NAD + and show that both metabolites compete for binding to the auto-inhibitory N-terminal armadillo repeat (ARM) domain of SARM1. We report structures of the SARM1 ARM domain bound to NMN and of the homo-octameric SARM1 complex in the absence of ligands. We show that NMN influences the structure of SARM1 and demonstrate via mutagenesis that NMN binding is required for injury-induced SARM1 activation and axon destruction. Hence, SARM1 is a metabolic sensor responding to an increased NMN/NAD + ratio by cleaving residual NAD +, thereby inducing feedforward metabolic catastrophe and axonal demise.
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    Journal Title
    Neuron
    DOI
    https://doi.org/10.1016/j.neuron.2021.02.009
    Subject
    Neurosciences
    Psychology
    Cognitive Sciences
    Publication URI
    http://hdl.handle.net/10072/402975
    Collection
    • Journal articles

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