Enrichment of <i>SARM1</i> alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders.

ABSTRACT: SARM1, a protein with critical NADase activity, is a central executioner in a conserved programme of axon degeneration. We report seven rare missense or in-frame microdeletion human SARM1 variant alleles in patients with amyotrophic lateral sclerosis (ALS) or other motor nerve disorders that alter the SARM1 auto-inhibitory ARM domain and constitutively hyperactivate SARM1 NADase activity. The constitutive NADase activity of these seven variants is similar to that of SARM1 lacking the entire ARM domain and greatly exceeds the activity of wild-type SARM1, even in the presence of nicotinamide mononucleotide (NMN), its physiological activator. This rise in constitutive activity alone is enough to promote neuronal degeneration in response to otherwise non-harmful, mild stress. Importantl

SUBMITTER: Gilley J 

PROVIDER: S-EPMC8735862 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature