Hereditary spastic paraplegias are heterogeneous neurodegenerative disorders. Understanding of their pathogenic mechanisms remains sparse, and therapeutic options are lacking. We characterized a mouse model lacking the Cyp2u1 gene, loss of which is known to be involved in a complex form of these diseases in humans. We showed that this model partially recapitulated the clinical and biochemical phenotypes of patients. Using electron microscopy, lipidomic, and proteomic studies, we identified vitamin B2 as a substrate of the CYP2U1 enzyme, as well as coenzyme Q, neopterin, and IFN-α levels as putative biomarkers in mice and fluids obtained from the largest series of CYP2U1-mutated patients reported so far. We also confirmed brain calcifications as a potential biomarker in patients. Our results suggest that CYP2U1 deficiency disrupts mitochondrial function and impacts proper neurodevelopment, which could be prevented by folate supplementation in our mouse model, followed by a neurodegenerative process altering multiple neuronal and extraneuronal tissues.

中文翻译：

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叶酸缺乏对 CYP2U1 功能丧失的影响

遗传性痉挛性截瘫是一种异质性神经退行性疾病。对其致病机制的了解仍然很少，并且缺乏治疗选择。我们描述了一种缺乏 Cyp2u1 基因的小鼠模型，已知该基因的缺失与人类这些复杂疾病有关。我们证明该模型部分概括了患者的临床和生化表型。使用电子显微镜、脂质组学和蛋白质组学研究，我们确定了维生素 B2 作为 CYP2U1 酶的底物，以及辅酶 Q、新蝶呤和 IFN-α 水平作为从最大系列 CYP2U1 获得的小鼠和体液中的推定生物标志物。迄今为止已报告的突变患者。我们还证实大脑钙化是患者的潜在生物标志物。我们的结果表明，CYP2U1 缺乏会破坏线粒体功能并影响正常的神经发育，这可以通过在我们的小鼠模型中补充叶酸来预防，随后发生改变多个神经元和神经元外组织的神经退行性过程。