Department of Human Molecular Genetics, Institute of Human Genetics, Heidelberg University Hospital, D-69120 Heidelberg, Germany.
Chica and Heinz Schaller Research Group, Institute for Anatomy and Cell Biology, D-69120 Heidelberg, Germany.
Proc Natl Acad Sci U S A. 2022 Feb 22;119(8). doi: 10.1073/pnas.2112852119.
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 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., , , , , and ) were dysregulated in the striatum of 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 mice, suggesting that insufficient energy supply and excessive oxidative stress underlie the cognitive and motor impairment in FOXP1 deficiency.
叉头框蛋白 P1（FOXP1）基因单倍体不足引起的 FOXP1 综合征是一种神经发育障碍，表现为运动功能障碍、智力残疾、自闭症和语言障碍。在这项研究中，我们使用小鼠模型来研究 FOXP1 综合征中的认知和运动缺陷是否与线粒体功能障碍和氧化应激有关。在这里，我们显示在线粒体生物发生和动力学中起作用的基因（例如， ， ， ， 和 ）在不同的出生后阶段在纹状体中失调。此外，这些动物表现出线粒体膜电位和复合物 I 活性降低，以及抗氧化剂超氧化物歧化酶 2（Sod2）和谷胱甘肽（GSH）的表达减少，导致氧化应激和脂质过氧化增加。这些特征可以解释我们在这些动物中观察到的神经突分支减少、学习和记忆、耐力和运动协调能力下降。总之，我们提供了小鼠中线粒体功能障碍的有力证据，表明 FOXP1 缺乏症中的认知和运动障碍的基础是能量供应不足和过度氧化应激。
