| First Author | Figley MD | Year | 2021 |
| Journal | Neuron | Volume | 109 |
| Issue | 7 | Pages | 1118-1136.e11 |
| PubMed ID | 33657413 | Mgi Jnum | J:305613 |
| Mgi Id | MGI:6706077 | Doi | 10.1016/j.neuron.2021.02.009 |
| Citation | Figley MD, et al. (2021) SARM1 is a metabolic sensor activated by an increased NMN/NAD(+) ratio to trigger axon degeneration. Neuron 109(7):1118-1136.e11 |
| abstractText | 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. |
