State Key Laboratory for Molecular and Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
University of Chinese Academy of Sciences, Beijing 100093, China.
Sci Adv. 2024 Apr 5;10(14):eadl2764. doi: 10.1126/sciadv.adl2764.
Despite seizure control by early high-dose pyridoxine (vitamin B6) treatment, at least 75% of pyridoxine-dependent epilepsy (PDE) patients with mutation still suffer from intellectual disability. It points to a need for additional therapeutic interventions for PDE beyond pyridoxine treatment, which provokes us to investigate the mechanisms underlying the impairment of brain hemostasis by ALDH7A1 deficiency. In this study, we show that ALDH7A1-deficient mice with seizure control exhibit altered adult hippocampal neurogenesis and impaired cognitive functions. Mechanistically, ALDH7A1 deficiency leads to the accumulation of toxic lysine catabolism intermediates, α-aminoadipic-δ-semialdehyde and its cyclic form, δ-1-piperideine-6-carboxylate, which in turn impair de novo pyrimidine biosynthesis and inhibit NSC proliferation and differentiation. Notably, supplementation of pyrimidines rescues abnormal neurogenesis and cognitive impairment in ALDH7A1-deficient adult mice. Therefore, our findings not only define the important role of ALDH7A1 in the regulation of adult hippocampal neurogenesis but also provide a potential therapeutic intervention to ameliorate the defective mental capacities in PDE patients with seizure control.
尽管早期大剂量吡哆醇（维生素 B6）治疗可控制癫痫发作，但至少 75%的突变相关吡哆醇依赖性癫痫（PDE）患者仍存在智力障碍。这表明除了吡哆醇治疗外，PDE 还需要其他治疗干预，这促使我们研究 ALDH7A1 缺乏导致的脑止血功能障碍的机制。在这项研究中，我们表明，癫痫得到控制的 ALDH7A1 缺陷小鼠表现出成年海马神经发生改变和认知功能受损。从机制上讲，ALDH7A1 缺乏会导致有毒赖氨酸代谢物中间产物的积累，即α-氨基己二酸-δ-亚醛及其环状形式δ-1-哌啶-6-羧酸，这反过来又会损害从头嘧啶生物合成并抑制 NSC 增殖和分化。值得注意的是，嘧啶的补充可挽救 ALDH7A1 缺陷成年小鼠的异常神经发生和认知障碍。因此，我们的发现不仅定义了 ALDH7A1 在调节成年海马神经发生中的重要作用，而且为改善癫痫得到控制的 PDE 患者的缺陷智力能力提供了一种潜在的治疗干预措施。
