한빛사 논문
Hyung-lok Chung,1,2,3 Michael F. Wangler,1,2,4 Paul C. Marcogliese,1,2 Juyeon Jo,2,5 Thomas A. Ravenscroft,1,2 Zhongyuan Zuo,1,2 Lita Duraine,3 Sina Sadeghzadeh,6 David Li-Kroeger,1,2 Robert E. Schmidt,7 Alan Pestronk,7 Jill A. Rosenfeld,1 Lindsay Burrage,1 Mitchell J. Herndon,7 Shan Chen,1 Members of Undiagnosed Diseases Network, Amelle Shillington,8,9 Marissa Vawter-Lee,9,10 Robert Hopkin,8,9 Jackeline Rodriguez-Smith,9,11 Michael Henrickson,9,11 Brendan Lee,1 Ann B. Moser,12 Richard O. Jones,12 Paul Watkins,12 Taekyeong Yoo,13 Soe Mar,14 Murim Choi,13,15 Robert C. Bucelli,16 Shinya Yamamoto,1,2,4,17 Hyun Kyoung Lee,2,4,5,17 Carlos E. Prada,8,9 Jong-Hee Chae,15 Tiphanie P. Vogel,18 and Hugo J. Bellen1,2,3,4,17,19,*
1Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
2Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
3Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA
4Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
5Department of Pediatrics, Section of Neurology, Baylor College of Medicine, Houston, TX 77030, USA
6Department of Psychology, Harvard University, Cambridge, MA 02138, USA
7Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, MO 63110, USA
8Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
9Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
10Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
11Division of Rheumatology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
12Division of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
13Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
14Department of Neurology, St. Louis Children’s Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA
15Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
16Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA
17Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA 18Department of Pediatrics, Section of Rheumatology, Baylor College of Medicine, Center for Human Immunobiology, Texas Children’s Hospital, Houston, TX 77030, USA
19Lead Contact
*Correspondence
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.
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