Constitutively active SARM1 variants that induce neuropathy are enriched in ALS patients

A Joseph Bloom,Jeffrey Milbrandt,Amy Strickland,Yo Sasaki,Xianrong Mao,Aaron Diantonio

doi:10.1186/s13024-021-00511-x

A Joseph Bloom, Jeffrey Milbrandt + Show 4 more

Open Access

https://doi.org/10.1186/s13024-021-00511-x

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Abstract

BackgroundIn response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase, SARM1. In healthy neurons SARM1 is autoinhibited, but single amino acid changes can abolish autoinhibition leading to constitutively active SARM1 enzymes that promote degeneration when expressed in cultured neurons.MethodsTo investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo.ResultsTwelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive NADase activity, including more than half of those that are unique to the ALS patients or that occur in multiple patients. There is a > 5-fold enrichment of constitutively active variants among patients compared to controls. Expression of constitutively active ALS-associated SARM1 alleles in cultured dorsal root ganglion (DRG) neurons is pro-degenerative and cytotoxic. Intrathecal injection of an AAV expressing the common SARM1 reference allele is innocuous to mice, but a construct harboring SARM1V184G, the constitutively active variant found most frequently among the ALS patients, causes axon loss, motor dysfunction, and sustained neuroinflammation.ConclusionsThese results implicate rare hypermorphic SARM1 alleles as candidate genetic risk factors for ALS and other neurodegenerative conditions.

Highlights

In response to injury, neurons activate a program of organized axon self-destruction initiated by the Nicotinamide adenine dinucleotide (NAD)+ hydrolase, Sterile alpha and Toll/Interleukin receptor (TIR) motif containing 1 (SARM1)
We identified a total of 30 rare SARM1 coding variants occurring exclusively in amyotrophic lateral sclerosis (ALS) patients, culled from three large publicly-accessible ALS consortia databases that include 8507 cases in total as of January 202041–43 (Table 1)
We further identified twelve rare SARM1 coding variants that occur in control individuals from these databases

Summary

Introduction

Neurons activate a program of organized axon self-destruction initiated by the NAD+ hydrolase, SARM1. Power to detect such associations is naturally attenuated for genes harboring low penetrance variants that contribute to risk without necessarily causing disease, which is relevant given the oligogenic nature of sporadic ALS [5] This difficulty is compounded when the functional consequences of rare variants cannot be predicted from sequence alone i.e. for genes where protein-truncating alleles are not assumed to be pathogenic [3], and all the more so when variants in the same gene may confer either increased disease risk or protection. In such cases, the power to detect significant associations can only be improved by systematically characterizing all the functional variants in a candidate gene [6]. We take such a hypothesis-driven approach to identify potentially pathogenic alleles of SARM1, a key driver of axon degeneration

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