Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms PMID: 32169171

ADC Targets in Oncology

2026-04-10

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.

Hyung-Lok Chung ¹ , Michael F Wangler ² , Paul C Marcogliese ³ , Juyeon Jo ⁴ , Thomas A Ravenscroft ³ , Zhongyuan Zuo ³ , Lita Duraine ⁵ , Sina Sadeghzadeh ⁶ , David Li-Kroeger ³ , Robert E Schmidt ⁷ , Alan Pestronk ⁷ , Jill A Rosenfeld ⁸ , Lindsay Burrage ⁸ , Mitchell J Herndon ⁷ , Shan Chen ⁸ , Members of Undiagnosed Diseases Network , Amelle Shillington ⁹ , Marissa Vawter-Lee ¹⁰ , Robert Hopkin ⁹ , Jackeline Rodriguez-Smith ¹¹ , Michael Henrickson ¹¹ , Brendan Lee ⁸ , Ann B Moser ¹² , Richard O Jones ¹² , Paul Watkins ¹² , Taekyeong Yoo ¹³ , Soe Mar ¹⁴ , Murim Choi ¹⁵ , Robert C Bucelli ¹⁶ , Shinya Yamamoto ¹⁷ , Hyun Kyoung Lee ¹⁸ , Carlos E Prada ⁹ , Jong-Hee Chae ¹⁹ , Tiphanie P Vogel ²⁰ , Hugo J Bellen ²¹

Affiliations

1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
2. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA.
3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
4. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA.
5. Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
6. Department of Psychology, Harvard University, Cambridge, MA 02138, USA.
7. Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
8. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
9. Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA.
10. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
11. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA; Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
12. Division of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
13. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
14. Department of Neurology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA.
15. Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea; Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
16. Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
17. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
18. Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA.
19. Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
20. Department of Pediatrics, Section of Rheumatology, Baylor College of Medicine, Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
21. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA; Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA; Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: [email protected].

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.