Wednesday, February 3, 2021

ACOX1 gain-of-function mutation

UPDATE Oct 2, 2019: Mitchell Herndon passed away on October 2, 2019. He was was taken off life support according to his final wishes after doctors discovered the disease had infiltrated his brain. He was surrounded by his family, and left in peace according to his mother Michele Herndon.


 A recent study led by researchers at Baylor College of Medicine reports that a hyperactive variant of enzyme ACOX1 produces elevated levels of toxic reactive oxygen species (ROS) and causes a previously unidentified late-onset neurodegenerative disorder. The team named this new syndrome “Mitchell disease” in reference to the first patient to be diagnosed with this disorder. 

Experiments using fruit flies revealed that Mitchell disease caused by a hyperactive ACOX1 enzyme and ACOX1 gene deficiency are molecularly very distinct disorders. The study also identified therapeutic strategies to successfully reverse the damages specific to each condition. 

In flies, bezafibrate, a commonly prescribed cholesterol-lowering drug, suppressed the symptoms of ACOX1 deficiency while N-acetylcysteine amide (NACA), an improved derivative of a widely available antioxidant supplement, N-acetyl cysteine (NAC), strongly reversed the toxic effects of hyperactive ACOX1 enzyme in Mitchell’s disease. The study appears in the journal Neuron. 

“The brain has large amounts of lipids, which are critical for the proper functioning of the nervous system. Abnormal breakdown of lipids in the brain and peripheral nervous system is associated with several neurodegenerative diseases,” said corresponding author Dr. Hugo J. Bellen professor at Baylor College of Medicine and investigator at the Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital and also a Howard Hughes Medical Institute investigator. 

In higher vertebrates and insects, very-long-chain-fatty acids (VLCFA) are exclusively broken down in small intracellular organelles called peroxisomes by a series of reactions initiated by an enzyme called Acyl-CoA oxidase 1 (ACOX1). Loss of ACOX1 in humans results in ACOX1 deficiency, which causes an early-onset fatal neuro-inflammatory disease and death at a young age.

Chung HL, Wangler MF, Marcogliese PC, Jo J, Ravenscroft TA, Zuo Z, Duraine L, Sadeghzadeh S, Li-Kroeger D, Schmidt RE, Pestronk A, Rosenfeld JA, Burrage L, Herndon MJ, Chen S; Members of Undiagnosed Diseases Network, Shillington A, Vawter-Lee M, Hopkin R, Rodriguez-Smith J, Henrickson M, Lee B, Moser AB, Jones RO, Watkins P, Yoo T, Mar S, Choi M, Bucelli RC, Yamamoto S, Lee HK, Prada CE, Chae JH, Vogel TP, Bellen HJ. 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. Epub 2020 Mar 12. PMID: 32169171; PMCID: PMC7289150.


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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