Loss or Gain of Function Mutations in ACOX1 Cause Axonal Loss Via Different Mechanisms
67 Pages Posted: 29 Aug 2019 Sneak Peek Status: Review CompleteMore...
ACOX1 (acyl-CoA oxidase 1) encodes the first and rate-limiting enzyme in very-long-chain fatty acid (VLCFA) β-oxidation in peroxisomes and produces H2O2. Unexpectedly, dACOX1 is mostly expressed and required in glia, and its loss in flies leads to developmental delay and pupal death. Flies that escape death exhibit a severely reduced lifespan, impaired synaptic transmission, and pronounced glial and axonal loss. Patients who carry a previously unidentified, de novo, heterozygous variant in ACOX1 (p.N237S) also exhibit axonal loss. However, this mutation causes increased levels of ACOX1 and reactive oxygen species in insulating glia in flies and Schwann cells in mice. Similarly, ACOX1 (p.N237S) patients exhibit a severe loss of Schwann cells, motor and sensory neurons. Treatment of flies, primary Schwann cells and a patient with an anti-oxidant suppresses these phenotypes. In summary, both loss and gain-of ACOX1 leads to glial and neuronal loss, but via different mechanisms and require different treatments.
Keywords: Personalized medicine, Mitchell Disease, Lipid metabolism, Very long chain fatty acids, ROS, Peroxisome, Schwann cell, Bezafibrate, Wrapping glial, Drosophila, ACOX1 deficiency, Undiagnosed Disease Network, Rare disease
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