Rare SARM1 Variants Linked to ALS and Motor Nerve Disorders: Preclinical Findings

Synopsis

SARM1 is a protein that breaks down NAD+, playing a key role in axon degeneration. Researchers found seven rare SARM1 gene variants in patients with ALS or other motor nerve disorders. These variants disrupt SARM1's auto-inhibitory region, causing it to be constantly overactive and break down NAD+ excessively—much more than the normal protein—even without the usual activator present. This high activity can cause nerve cells to degenerate in response to mild stress that would otherwise be harmless. These specific variants were found only in patients and are strongly linked to disease, supporting SARM1's role in motor neuron disorders. The patients showed diverse symptoms and ages of onset, suggesting complex disease mechanisms.

Journal

eLife