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Enrichment of SARM1 alleles encoding variants with constitutively hyperactive NADase in patients with ALS and other motor nerve disorders

Published version
Peer-reviewed

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Authors

Gilley, Jonathan 
Coleman, michael 
Jackson, Oscar 

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. Importantly, these strong gain-of-function alleles are completely patient-specific in the cohorts studied and show a highly significant association with disease at the single gene level. These findings of disease-associated coding variants that alter SARM1 function build on previously reported genome-wide significant association with ALS for a neighbouring, more common SARM1 intragenic single nucleotide polymorphism (SNP) to support a contributory role of SARM1 in these disorders. A broad phenotypic heterogeneity and variable age-of-onset of disease among patients with these alleles also raises intriguing questions about the pathogenic mechanism of hyperactive SARM1 variants.

Description

Funder: Motor Neurone Disease Association; FundRef: http://dx.doi.org/10.13039/501100000406


Funder: NIHR Biomedical Research Centre, Royal Marsden NHS Foundation Trust/Institute of Cancer Research; FundRef: http://dx.doi.org/10.13039/100014461


Funder: EU Joint Programme – Neurodegenerative Disease Research; FundRef: http://dx.doi.org/10.13039/100013278


Funder: Robert Packard Center for ALS Research, Johns Hopkins University; FundRef: http://dx.doi.org/10.13039/100012312

Keywords

ALS, NADase, SARM1, genetics, genomics, human, neuroscience, risk allele, Adult, Aged, Alleles, Amyotrophic Lateral Sclerosis, Animals, Armadillo Domain Proteins, Cytoskeletal Proteins, Female, Humans, Male, Mice, Middle Aged, Motor Neuron Disease, NAD+ Nucleosidase, Nicotinamide Mononucleotide

Journal Title

eLife

Conference Name

Journal ISSN

2050-084X
2050-084X

Volume Title

10

Publisher

eLife Sciences Publications Ltd
Sponsorship
Biotechnology and Biological Sciences Research Council (BB/S009582/1)
Medical Research Council (MR/N004582/1)
Wellcome Trust (220906/Z/20/Z)