RESUMO
FOXP1 syndrome caused by haploinsufficiency of the forkhead box protein P1 (FOXP1) gene is a neurodevelopmental disorder that manifests motor dysfunction, intellectual disability, autism, and language impairment. In this study, we used a Foxp1+/- mouse model to address whether cognitive and motor deficits in FOXP1 syndrome are associated with mitochondrial dysfunction and oxidative stress. Here, we show that genes with a role in mitochondrial biogenesis and dynamics (e.g., Foxo1, Pgc-1α, Tfam, Opa1, and Drp1) were dysregulated in the striatum of Foxp1+/- mice at different postnatal stages. Furthermore, these animals exhibit a reduced mitochondrial membrane potential and complex I activity, as well as decreased expression of the antioxidants superoxide dismutase 2 (Sod2) and glutathione (GSH), resulting in increased oxidative stress and lipid peroxidation. These features can explain the reduced neurite branching, learning and memory, endurance, and motor coordination that we observed in these animals. Taken together, we provide strong evidence of mitochondrial dysfunction in Foxp1+/- mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.
Assuntos
Fatores de Transcrição Forkhead/genética , Deficiência Intelectual/genética , Transtornos Motores/genética , Proteínas Repressoras/genética , Animais , Transtorno do Espectro Autista/genética , Transtorno Autístico/metabolismo , Cognição/fisiologia , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/deficiência , Fatores de Transcrição Forkhead/metabolismo , Haploinsuficiência/genética , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/genética , Mitocôndrias/metabolismo , Atividade Motora/genética , Transtornos Motores/metabolismo , Transtornos do Neurodesenvolvimento/metabolismo , Neurogênese , Estresse Oxidativo/fisiologia , Proteínas Repressoras/deficiência , Proteínas Repressoras/metabolismoRESUMO
Diabetes mellitus is a set of complex metabolic disorders characterized by chronic hyperglycaemic condition due to defective insulin secretion (Type 1) and action (Type 2), which leads to serious micro and macro-vascular damage, inflammation, oxidative and nitrosative stress and a deranged energy homeostasis due to imbalance in the glucose and lipid metabolism. Moreover, patient with diabetes mellitus often showed the nervous system disorders known as diabetic encephalopathy. The precise pathological mechanism of diabetic encephalopathy by which it effects the central nervous system directly or indirectly causing the cognitive and motor impairment, is not completely understood. However, it has been speculated that like other extracerebellar tissues, oxidative and nitrosative stress may play significant role in the pathogenesis of diabetic encephalopathy. Therefore, the present review aimed to explain the possible association of the oxidative and nitrosative stress caused by the chronic hyperglycaemic condition with the central nervous system complications of the type 2 diabetes mellitus induced diabetic encephalopathy.