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.