CoQ10 Analogue Ameliorates Mitochondrial Dysfunction in an Angelman Syndrome Mouse Model

Angelman Syndrome (AS) is a neurodegenerative disorder, symptoms of which include speech impairment, intellectual disability, epilepsy, impaired motor coordination, and microcephaly. AS is caused by a number of genetic alterations, predominantly a deletion of the E6-AP Ubiquitin E3 ligase (UBE3A) gene on chromosome 15q11-13 of the maternal allele. Genomic imprinting of the paternal allele causes UBE3A expression to be silenced in certain regions of the brain, mainly the hippocampus and cerebellum. Previous studies in the maternally-deficient Ube3a AS mouse model revealed a structural mitochondrial defect and significantly decreased activity of complex III, critical for the electron transport chain (ETC) in the hippocampus. In this study, we analyzed the effects of a Coenzyme Q₁₀ (CoQ₁₀) analog, Idebenone, in this mouse model. We hypothesized Idebenone would improve the flow of electrons in the ETC and alleviate the symptoms of AS. We analyzed changes in coordination and behavior post-treatment with a variety of tests. We found an improvement in motor coordination with the Rotarod assay and increased activity in novel environments with a marble burying assay in Ube3a AS mice after 3 months of Idebenone treatment. Immunohistochemistry (IHC) and Western blot revealed increased expression of mitochondrial complex III and IV in the hippocampus of idebenone treated Ube3a AS mice. We are currently analyzing any changes in expression of complex I and II. These results suggest that treatment with a CoQ₁₀ analogue, such as idebenone extends not only to classic mitochondrial diseases, such as Leber’s hereditary optic neuropathy (LHON), but potentially could alleviate symptoms in patients with diseases such as Angelman syndrome in which mitochondrial function is perturbed.