title: Administration of CoQ10 analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome.
abstract: 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. CoQ10 supplementation restores the electron flow to the mitochondrial respiratory chain (MRC) to ultimately increase mitochondrial antioxidant capacity. A number of recent studies with CoQ10 analogues seem promising in providing therapeutic benefit to patients with a variety of disorders. CoQ10 therapy has been reported to be safe and relatively well-tolerated at doses as high as 3000mg/day in patients with disorders of CoQ10 biosynthesis and MRC disorders. Herein, we report administration of idebenone, a potent CoQ10 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 CoQ10 analogue. These findings may further elucidate possible cellular and molecular mechanism(s) and ultimately a clinical therapeutic approach/benefit for patients with Angelman syndrome.
authors: Department of Pediatrics, Division of Genetics and Genomics, 2501 Hewitt Hall, University of California-Irvine, Irvine, CA 92697, USA. Electronic address: kllewell@uci.edu.
authors: Katrina J
authors: KJ
authors: Llewellyn
authors: Department of Pediatrics, Division of Genetics and Genomics, 2501 Hewitt Hall, University of California-Irvine, Irvine, CA 92697, USA.
authors: Angèle
authors: A
authors: Nalbandian
authors: Department of Pediatrics, Division of Genetics and Genomics, 2501 Hewitt Hall, University of California-Irvine, Irvine, CA 92697, USA.
authors: Arianna
authors: A
authors: Gomez
authors: Department of Anatomy & Neurobiology, Gillespie Hall, University of California-Irvine, Irvine, CA 92697, USA.
authors: Don
authors: D
authors: Wei
authors: Department of Pediatrics, Division of Genetics and Genomics, 2501 Hewitt Hall, University of California-Irvine, Irvine, CA 92697, USA.
authors: Naomi
authors: N
authors: Walker
authors: Department of Pediatrics, Division of Genetics and Genomics, 2501 Hewitt Hall, University of California-Irvine, Irvine, CA 92697, USA. Electronic address: vkimonis@uci.edu.
authors: Virginia E
authors: VE
authors: Kimonis
mesh_terms: D017204:Angelman Syndrome / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004579:Electron Transport / Q000187:drug effects*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009043:Motor Activity / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D014451:Ubiquinone / Q000008:administration & dosage / Q000031:analogs & derivatives*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000975:Antioxidants; D014451:Ubiquinone; C502429:Ube3a protein, mouse; D044767:Ubiquitin-Protein Ligases; C036619:idebenone
keywords: Angelman syndrome; Coenzyme Q(10) analogue; Cytochrome oxidase subunit IV; Glutathione disulfide; Idebenone; Mitochondrial respiratory chain; Neurodegenerative disorder