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Loss or Gain of Function Mutations in ACOX1 Cause Axonal Loss Via Different Mechanisms

67 Pages Posted: 29 Aug 2019 Sneak Peek Status: Review Complete

See all articles by Hyunglok Chung

Hyunglok Chung

Baylor College of Medicine - Howard Hughes Medical Institute; Baylor College of Medicine - Department of Molecular and Human Genetics; Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Michael F. Wangler

Baylor College of Medicine - Department of Molecular and Human Genetics

Paul Marcogliese

Baylor College of Medicine - Department of Molecular and Human Genetics

Juyeon Jo

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Thomas Ravenscoft

Baylor College of Medicine - Department of Molecular and Human Genetics

Lita Duraine

Baylor College of Medicine - Howard Hughes Medical Institute

Sina Sadeghzadeh

Harvard University - Department of Psychology

David Li-Kroeger

Baylor College of Medicine - Department of Molecular and Human Genetics

Robert E. Schmidt

Washington University in St. Louis - Division of Neuropathology

Alan Pestronk

Washington University in St. Louis - Division of Neuropathology

Jill Rosenfeld

Baylor College of Medicine - Department of Molecular and Human Genetics

Lindsay Burrage

Baylor College of Medicine - Department of Molecular and Human Genetics

Mitchell Herndon

Washington University in St. Louis - Division of Neuropathology

Shan Chen

Baylor College of Medicine - Department of Molecular and Human Genetics

Undiagnosed Diseases Network Group

Amelle Shillington

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Marissa Vawater-Lee

University of Cincinnati - Department of Pediatrics

Robert Hopkin

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Jackeline Rodriguez-Smith

University of Cincinnati - Department of Pediatrics

Michael Henrickson

University of Cincinnati - Department of Pediatrics

Brendan Lee

Baylor College of Medicine - Department of Molecular and Human Genetics

Ann Moser

Johns Hopkins University - Division of Neurogenetics

Richard O. Jones

Johns Hopkins University - Division of Neurogenetics

Taekyeong Yoo

Seoul National University - Department of Biomedical Sciences

Soe Mar

Washington University in St. Louis - Department of Neurology

Murim Choi

Seoul National University - Department of Biomedical Sciences

Robert Bucelli

Washington University in St. Louis - Department of Neurology

Shinya Yamamoto

Baylor College of Medicine - Department of Molecular and Human Genetics

Hyun Kyung Lee

Seoul National University - Department of Pediatrics

Carlos Prada

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Jong-Hee Chae

Seoul National University - Department of Pediatrics

Tiphanie Vogel

University of Chicago - Section of Rheumatology

Hugo Bellen

Baylor College of Medicine - Howard Hughes Medical Institute; Baylor College of Medicine - Department of Molecular and Human Genetics; Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute; Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program; Baylor University, College of Medicine, Program in Developmental Biology

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Abstract

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

Suggested Citation

Chung, Hyunglok and Wangler, Michael F. and Marcogliese, Paul and Jo, Juyeon and Ravenscoft, Thomas and Duraine, Lita and Sadeghzadeh, Sina and Li-Kroeger, David and Schmidt, Robert E. and Pestronk, Alan and Rosenfeld, Jill and Burrage, Lindsay and Herndon, Mitchell and Chen, Shan and Group, Undiagnosed Diseases Network and Shillington, Amelle and Vawater-Lee, Marissa and Hopkin, Robert and Rodriguez-Smith, Jackeline and Henrickson, Michael and Lee, Brendan and Moser, Ann and Jones, Richard O. and Yoo, Taekyeong and Mar, Soe and Choi, Murim and Bucelli, Robert and Yamamoto, Shinya and Lee, Hyun Kyung and Prada, Carlos and Chae, Jong-Hee and Vogel, Tiphanie and Bellen, Hugo, Loss or Gain of Function Mutations in ACOX1 Cause Axonal Loss Via Different Mechanisms (August 27, 2019). NEURON-D-19-01325. Available at SSRN: https://ssrn.com/abstract=3443598 or http://dx.doi.org/10.2139/ssrn.3443598
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hyunglok Chung

Baylor College of Medicine - Howard Hughes Medical Institute

Houston, TX 77030
United States

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

Houston, TX
United States

Michael F. Wangler

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Paul Marcogliese

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Juyeon Jo

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute

6621 Fannin St
Houston, TX 77030
United States

Thomas Ravenscoft

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Lita Duraine

Baylor College of Medicine - Howard Hughes Medical Institute

Houston, TX 77030
United States

Sina Sadeghzadeh

Harvard University - Department of Psychology

1875 Cambridge Street
Cambridge, MA 02138
United States

David Li-Kroeger

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Robert E. Schmidt

Washington University in St. Louis - Division of Neuropathology

St. Louis, MO 63110
United States

Alan Pestronk

Washington University in St. Louis - Division of Neuropathology

St. Louis, MO 63110
United States

Jill Rosenfeld

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Lindsay Burrage

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Mitchell Herndon

Washington University in St. Louis - Division of Neuropathology

St. Louis, MO 63110
United States

Shan Chen

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Amelle Shillington

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Cincinnati, OH 45229
United States

Marissa Vawater-Lee

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Robert Hopkin

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Cincinnati, OH 45229
United States

Jackeline Rodriguez-Smith

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Michael Henrickson

University of Cincinnati - Department of Pediatrics

Cincinnati, OH 45221-0389
United States

Brendan Lee

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Ann Moser

Johns Hopkins University - Division of Neurogenetics

Baltimore, MD 21205
United States

Richard O. Jones

Johns Hopkins University - Division of Neurogenetics

Baltimore, MD 21205
United States

Taekyeong Yoo

Seoul National University - Department of Biomedical Sciences

Seoul
Korea, Republic of (South Korea)

Soe Mar

Washington University in St. Louis - Department of Neurology

St Louis, MO 63110
United States

Murim Choi

Seoul National University - Department of Biomedical Sciences

Seoul
Korea, Republic of (South Korea)

Robert Bucelli

Washington University in St. Louis - Department of Neurology

St. Louis, MO
United States

Shinya Yamamoto

Baylor College of Medicine - Department of Molecular and Human Genetics

Houston, TX 77030
United States

Hyun Kyung Lee

Seoul National University - Department of Pediatrics ( email )

Seoul
Korea, Republic of (South Korea)

Carlos Prada

Cincinnati Children's Hospital Medical Center - Division of Human Genetics

Cincinnati, OH 45229
United States

Jong-Hee Chae

Seoul National University - Department of Pediatrics

Seoul
Korea, Republic of (South Korea)

Tiphanie Vogel

University of Chicago - Section of Rheumatology

United States

Hugo Bellen (Contact Author)

Baylor College of Medicine - Howard Hughes Medical Institute ( email )

Houston, TX 77030
United States

Baylor College of Medicine - Department of Molecular and Human Genetics ( email )

Houston, TX 77030
United States

Texas Children's Hospital - Jan and Dan Duncan Neurologic Research Institute ( email )

Houston, TX
United States

Baylor University, College of Medicine, MD/PhD Medical Scientist Training Program and MHG Graduate Program ( email )

Houston, TX
United States

Baylor University, College of Medicine, Program in Developmental Biology ( email )

Houston, TX 77030
United States

No contact information is available for Undiagnosed Diseases Network Group

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