biostudies-literatureChung HLIntramural NIH HHSNICHD NIH HHSHoward Hughes Medical InstituteNICHDNIHNIH Common FundORIPCIHRNHGRI NIH HHSNINDS NIH HHSNMSSNIH HHSNIGMS NIH HHS589-606.e6https://www.ebi.ac.uk/biostudies/studies/S-EPMC7289150biostudies-literatureUnknown106(4)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, treatmenNeuronLoss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.PMC7289150R24 OD022005U54 NS093793RG1508-08406R24OD022005R01 GM067858P40 OD018537U54NS093793MFE-164712P40OD018537U54HD083092P50 HD103555U54 HD083092Z01 BC010425U01 HG007709U01HG007709Schmidt REZuo ZLi-Kroeger DRosenfeld JAJones ROChoi MLee BBucelli RCRavenscroft TAHenrickson MPestronk AShillington ALee HKMar SVogel TPChen SPrada CEChung HLVawter-Lee MMembers of Undiagnosed Diseases NetworkMarcogliese PCHopkin RWatkins PYamamoto SChae JHJo JRodriguez-Smith JMoser ABSadeghzadeh SDuraine LWangler MFYoo TBurrage LHerndon MJBellen HJfalseLoss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.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, treatmen2020-01-01T00:00:00Z2020 May2026-05-07T17:57:52.26Z2025-04-03T23:47:54.433ZS-EPMC72891503216917110.1016/j.neuron.2020.02.021