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)
Year published
2021
Metadata
Show full item recordAbstract
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 ...
View more >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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View more >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
Subject
Neurosciences
Psychology
Cognitive Sciences