Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms

Neuron. 2020 May 20;106(4):589-606.e6. doi: 10.1016/j.neuron.2020.02.021. Epub 2020 Mar 12.

Abstract

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 H2O2 production. Unexpectedly, Drosophila (d) ACOX1 is mostly expressed and required in glia, and loss of ACOX1 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 antioxidant suppressed the p.N237S-induced neurodegeneration. In summary, both loss and gain of ACOX1 lead to glial and neuronal loss, but different mechanisms are at play and require different treatments.

Keywords: ACOX1 deficiency; Drosophila; NACA; ROS; Schwann cells; antioxidant NACA; axonal dystrophy; fatty acid peroxidation; very long chain fatty acids; wrapping glia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyl-CoA Oxidase / genetics*
  • Animals
  • Axons / enzymology*
  • Axons / pathology
  • Drosophila
  • Humans
  • Mice
  • Mutation
  • Nerve Degeneration / enzymology
  • Nerve Degeneration / genetics*
  • Neuroglia / enzymology*
  • Neuroglia / pathology
  • Rats

Substances

  • Acyl-CoA Oxidase