Fruit flies provide insight on ACOX1-related neurodegenerative disorders

Fruit flies provide insight on ACOX1-related neurodegenerative disorders

A 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." Hugo J. Bellen, corresponding author, 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. A medical mystery This study began when a patient with puzzling neurological symptoms enrolled in the Undiagnosed Diseases Network (UDN) at the suggestion of Drs. Tiphanie Vogel, Soe Mar and Robert Buccelli, his healthcare providers and co-authors of this study. On comparing the patient's and his parents' DNA, the team identified a mutation in the patient that resulted in a single amino acid substitution (N237S) in the ACOX1 protein. This change was seen only in the patient and was not present in either of his parents' DNA, indicating that the patient had a de novo, or new, mutation on this gene. With the help of an online gene-matching tool, GeneMatcher, the team found two more patients who had the same new mutation in the ACOX1 gene. All three patients, who ranged from 3 to 12 years old at the time of disease onset, had remarkably similar clinical features, including degeneration of peripheral nerves that caused a progressive loss of mobility and hearing. The three individuals had identical variants, a clear indication that ACOX1 dysfunction likely was the cause of the symptoms. However, this finding initially baffled the researchers - the only known ACOX1-related disorder described in the medical literature at that time presented earlier in infancy with seizures, severe cognitive decline, neuro-inflammation and accumulation of VLCFA in plasma and, more importantly, was caused by the lack of the protein - none of which was true for these three patients. Fruit flies solve the medical mystery Related Stories



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