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

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• Neurons initiate axon self-destruction via the NAD+ hydrolase SARM1 in response to injury.
• SARM1 is normally autoinhibited, but mutations can lead to constitutive activity, promoting neuronal degeneration.

Purpose of the Study:

• Investigate if naturally occurring human SARM1 variants disrupt autoinhibition.
• Determine if these variants contribute to neurodegenerative disease risk, specifically amyotrophic lateral sclerosis (ALS).

Main Methods:

• Assayed enzymatic activity of 42 rare SARM1 alleles from ALS patients and controls.
• Injected mice intrathecally with SARM1 constructs to test in vivo neurodegeneration capacity.

Main Results:

• 12 of 42 SARM1 variants showed constitutive NADase activity; over half were unique to or frequent in ALS patients.
• Constitutively active ALS-associated SARM1 alleles were pro-degenerative in cultured neurons.
• In mice, a constitutively active SARM1 variant (SARM1^V184G) caused axon loss, motor deficits, and neuroinflammation.

Conclusions:

• Rare, hyperactive SARM1 alleles are implicated as genetic risk factors for ALS.
• These findings suggest a role for SARM1 variants in other neurodegenerative conditions.