PDF(Pubmed)
Abstract：
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a neurometabolic disorder caused by ALDH5A1 mutations presenting with autism and epilepsy. SSADHD leads to impaired GABA metabolism and results in accumulation of GABA and γ-hydroxybutyrate (GHB), which alter neurotransmission and are thought to lead to neurobehavioral symptoms. However, why increased inhibitory neurotransmitters lead to seizures remains unclear. We used induced pluripotent stem cells from SSADHD patients (one female and two male) and differentiated them into GABAergic and glutamatergic neurons. SSADHD iGABA neurons show altered GABA metabolism and concomitant changes in expression of genes associated with inhibitory neurotransmission. In contrast, glutamatergic neurons display increased spontaneous activity and upregulation of mitochondrial genes. CRISPR correction of the pathogenic variants or SSADHD mRNA expression rescue various metabolic and functional abnormalities in human neurons. Our findings uncover a previously unknown role for SSADHD in excitatory human neurons and provide unique insights into the cellular and molecular basis of SSADHD and potential therapeutic interventions.
摘要：
琥珀酸半醛脱氢酶缺乏症（SSADHD）是由表现为自闭症和癫痫的ALDH5A1突变引起的神经代谢紊乱。SSADHD导致GABA代谢受损，并导致GABA和γ-羟基丁酸（GHB）的积累，改变神经传递，被认为会导致神经行为症状。然而,抑制性神经递质增加导致癫痫发作的原因尚不清楚。我们使用来自SSADHD患者（一名女性和两名男性）的诱导多能干细胞，并将其分化为GABA能和谷氨酸能神经元。SSADHDiGABA神经元显示GABA代谢改变以及与抑制性神经传递相关的基因表达的伴随变化。相比之下,谷氨酸能神经元显示增加的自发活动和线粒体基因的上调。致病变体或SSADHDmRNA表达的CRISPR校正拯救了人类神经元中的各种代谢和功能异常。我们的发现揭示了以前未知的SSADHD在兴奋性人类神经元中的作用，并为SSADHD的细胞和分子基础以及潜在的治疗干预提供了独特的见解。
