Axonal death 1: Wallerian Degeneration in Human Disease

08 Nov 2019
09:00 - 09:45

Axonal death 1: Wallerian Degeneration in Human Disease

Axons degenerate before the neuronal soma in many neurodegenerative diseases, including ALS. Whether this reflects pathogenic events within the axon itself or a failure of support by the soma, maintaining axonal connectivity is essential for effective therapy.

Studies of Wallerian degeneration after axon injury have revealed a detailed molecular pathway that regulates axon survival and degeneration, also in some disorders not involving physical injury. At the core of this pathway are two opposing enzymes in NAD metabolism. NMNAT2 synthesizes NAD and is essential for axon survival. SARM1 degrades NAD and promotes axon degeneration. Nmnat2 null mice die at birth due to a failure to grow long axons, but simultaneous deletion of Sarm1 completely rescues them, allowing mice and their axons to survival for a normal lifespan. Low Nmnat2 expression causes early-onset sensory and late-onset motor deficiencies and makes axons more vulnerable to neurotoxins such as vincristine.

We recently identified human NMNAT2 loss-of-function (LoF) mutations in two disorders: biallelic null mutation in an apparently neurological stillbirth phenotype and homozygous partial loss-of-function in polyneuropathy with erythromelalgia and reduced muscle action potential. We found further NMNAT2 LoF and SARM1 gain-of-function mutations that are likely to be risk alleles for neurological disease, and SARM1 LoF mutations that are protective, even at heterozygosity. Together with substantial variation in gene expression, this results in a spectrum of axon vulnerability in the human population, ranging from pathogenic mutations through risk alleles to relative resistance likely to modify disease outcome in many disorders. By understanding these effects and developing specific biomarkers, we can define which specific human disorders involve the Wallerian pathway, and identify individuals at risk. Drugs blocking Wallerian degeneration can then be optimally targeted for clinical trials and personalized medicine.