Administration of CoQ(10) analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome

作者：Llewellyn Katrina J^*; Nalbandian Angele; Gomez Arianna; Wei Don; Walker Naomi; Kimonis Virginia E

来源：Neurobiology of Disease, 2015, 76: 77-86.

DOI：10.1016/j.nbd.2015.01.005

• Neurodegenerative disorder
• Angelman syndrome
• Mitochondrial respiratory chain
• Coenzyme Q(10) analogue
• Idebenone
• Cytochrome oxidase subunit IV
• Glutathione disulfide

Genetic defects in the UBE3A gene, which encodes for the imprinted E6-AP ubiquitin E3 ligase (UBE3A), is responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder which arises in 1 out of every 12,000-20,000 births. Classical symptoms of AS include delayed development, impaired speech, and epileptic seizures with characteristic electroencephalography (EEG) readings. We have previously reported impaired mitochondrial structure and reduced complex III in the hippocampus and cerebellum in the Ube3a(m-/P+) mice. CoQ(10) supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ(10) analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ(10) therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000 mg/day in patients with disorders of CoQ(10) biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ(10) analogue, to the Ube3a(m-/p+) mouse model corrects motor coordination and anxiety levels, and also improves the expression of complexes III and IV in hippocampus CA1 and CA2 neurons and cerebellum in these Ube3a(m-/P+) mice. However, treatment with idebenone illustrated no beneficial effects in the reduction of oxidative stress. To our knowledge, this is the first study to suggest an improvement in mitochondrial respiratory chain dysfunction via bioenergetics modulation with a CoQ(10) analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome.

• 出版日期2015-4