Lipid Metabolism and Axon Degeneration: An ACOX1 Balancing Act

ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme of the very-long-chain fatty acid (VLCFA) β-oxidation pathway in peroxisomes and leads to H(2)O(2) production. Unexpectedly, dACOX1 is mostly expressed and required in glia, and loss of dACOX1 leads to developmental delay, pupal death, reduced lifespan, impaired synaptic transmission, and glial and axonal loss. Patients who carry a previously unidentified, de novo, dominant variant in ACOX1 (p.N237S) also exhibit glial loss. However, this mutation causes increased levels of ACOX1 protein and function resulting in elevated levels of reactive oxygen species in glia in flies and murine Schwann cells. ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells and neurons. However, treatment of flies and primary Schwann cells with an anti-oxidant suppressed the p.N237S induced neurodegeneration. In summary, both loss and gain of ACOX1 leads to glial and neuronal loss, but different mechanisms are at play and require different treatments.