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

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Loss- or Gain-of-Function Mutations in ACOX1 Cause Axonal Loss via Different Mechanisms.
Neuron ( IF 14.7 ) Pub Date : 2020-03-12 , 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 , , 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

Affiliation

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.
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 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.
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.
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030, USA.
Department of Psychology, Harvard University, Cambridge, MA 02138, USA.
Department of Pathology and Immunology, Division of Neuropathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
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.
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.
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.
Division of Neurogenetics, Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Neurology, St. Louis Children's Hospital, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
Department of Neurology, Washington University School of Medicine, St. Louis, MO 63110, USA.
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.
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.
Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
Department of Pediatrics, Section of Rheumatology, Baylor College of Medicine, Center for Human Immunobiology, Texas Children's Hospital, Houston, TX 77030, USA.
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.

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.

中文翻译：

ACOX1 中功能丧失或获得的突变通过不同机制导致轴突损失。

ACOX1（酰基辅酶A氧化酶1）编码过氧化物酶体中极长链脂肪酸（VLCFA）β-氧化途径的第一个限速酶，并导致H2O2的产生。出乎意料的是，果蝇 (d) ACOX1 主要在神经胶质细胞中表达和需要，ACOX1 的缺失会导致发育迟缓、蛹死亡、寿命缩短、突触传递受损以及神经胶质细胞和轴突损失。携带先前未识别的 ACOX1 新显性变异 (p.N237S) 的患者也表现出神经胶质细胞丢失。然而，这种突变会导致 ACOX1 蛋白和功能水平升高，从而导致果蝇和鼠雪旺细胞的神经胶质细胞中活性氧水平升高。 ACOX1 (p.N237S) 患者表现出雪旺细胞和神经元的严重损失。然而，用抗氧化剂处理果蝇和原代雪旺细胞可抑制 p.N237S 诱导的神经变性。总之，ACOX1 的丢失和增加都会导致神经胶质和神经元损失，但发挥作用的机制不同，需要不同的治疗。

更新日期：2020-03-12

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