Administration of CoQ₁₀ analogue ameliorates dysfunction of the mitochondrial respiratory chain in a mouse model of Angelman syndrome

Highlights

• The Ube3a gene is responsible for Angelman syndrome, a neurodegenerative disorder.

• Mitochondrial dysfunction and reduced complex III is observed in Ube3a^m −/p + mice.

• CoQ₁₀ restores the electron flow to the mitochondrial respiratory chain.

• Idebenone, a CoQ₁₀ analogue ameliorates mitochondrial phenotype in Ube3a^m −/p + mice.

• These studies may have a therapeutic benefit for patients with 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 3000 mg/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.

Introduction

Genetic defects in the UBE3A gene which encodes for E6-AP ubiquitin-protein ligase E3A (UBE3A), also known as E6-AP ubiquitin protein ligase, are responsible for the occurrence of Angelman syndrome (AS), a neurodegenerative disorder that arises in 1 in every 12,000–20,000 births (Hasegawa et al., 2012, Kishino et al., 1997, Knoll et al., 1989). Symptoms of AS include delayed development, severely impaired speech, ataxia, microcephaly and epileptic seizures with characteristic EEG readings (Bailus and Segal, 2014, Bird, 2014). Maternal deletions or paternal uniparental disomy of chromosomal 15q11-13 region accounts for 70% and 7%, respectively of Angelman syndrome. An additional 11% is due to point mutations or deletions of the UBE3A gene and 3% is accounted for by imprinting center defects (Kishino et al., 1997, Knoll et al., 1989, Jiang et al., 1998a, Jiang et al., 1998b, Nicholls et al., 1998).

Ubiquitin E3 ligase is important in several cellular functions, including protein degradation, protein transport, endocytosis and protein–protein interactions. Jiang et al. (1998a) generated and characterized the Ube3a^m −/p + as an Angelman mouse model, having a deletion of the maternal UBE3A copy (Jiang et al., 1998a, Jiang et al., 1998b). Due to paternal imprinting, the UBE3A gene is silenced in certain brain regions, including the hippocampus and cerebellum, resulting in a lack of the UBE3A protein expression (Kishino et al., 1997, Jiang et al., 1998a). These mice exhibit pathology characteristic of Angelman syndrome, including motor coordination issues (ataxia), microcephaly, and epileptic-like seizures. These mice also display defects in the hippocampal long-term potentiation and cerebellar motor function (Huang et al., 2013, Gabriel et al., 1999). Our previous studies have demonstrated that hippocampal mitochondria of Ube3a^m −/p + mice are small and dense with disorganized cristae. These mice depict a reduction of complex III activity in the hippocampal region of the brain (Su et al., 2011). Several diseases with similar symptoms to AS, such as Rett syndrome have mitochondrial abnormalities (Condie et al., 2010, Gold et al., 2014). Our initial results that were suggestive of mitochondrial dysfunction in human AS led to this current investigation.

Idebenone is a CoQ₁₀ analogue, the predominant form of ubiquinone in humans. To date, the only agents which have shown some therapeutic potential have been CoQ₁₀ and its synthetic analogues. Idebenone is currently being used for the treatment of mitochondrial respiratory chain (MRC) disorders, which have been difficult to treat. We report that administration of idebenone, to the Ube3a^m −/p + mouse system corrects motor coordination and anxiety levels, but does not affect brain size, sociability or memory by novel object recognition (NOR) assay. We report that CoQ₁₀ treatment also improves the expression of complexes III and IV in the neurons of hippocampus CA1, CA2, and CA3 regions of the Ube3a^m −/p + mice. In addition, we report that oxidative stress measured by levels of glutathione disulfide (GSSG:GSH) and 4-HNE were increased in the cerebellum and hippocampus of Ube3a^m −/p + mice, when compared to WT controls. To our knowledge, this is the first study to suggest an improvement in the dysfunction of the mitochondrial respiratory chain with a CoQ₁₀ analogue, further elucidating a possible cellular/molecular mechanism(s) and ultimately potential therapeutic benefits for patients with Angelman syndrome.