Koh Byumseok, Kim Young Eun, Park Sung Bum, Kim Seong Soon, Lee Jangjae, Jo Jeong Hyeon, Lee KyungJin, Bae Dong Hyuck, Kim Tae-Young, Cho Sung-Hee, Bae Myung Ae, Kang Dukjin, Kim Ki Young
Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), 141 Gajeong-ro, Yuseong-gu, Daejeon 34114, Republic of Korea.
Group for Biometrology, Korea Research Institute of Standards and Science (KRISS), 267 Gajeong-ro, Yuseong-gu, Daejeon 34113, Republic of Korea.
ACS Omega. 2024 Sep 13;9(38):39804-39816. doi: 10.1021/acsomega.4c05039. eCollection 2024 Sep 24.
This study investigates the impact of sodium channel protein type 1 subunit alpha (SCN1A) gene knockout (SCN1A KO) on brain development and function using cerebral organoids coupled with a multiomics approach. From comprehensive omics analyses, we found that SCN1A KO organoids exhibit decreased growth, dysregulated neurotransmitter levels, and altered lipidomic, proteomic, and transcriptomic profiles compared to controls under matrix-free differentiation conditions. Neurochemical analysis reveals reduced levels of key neurotransmitters, and lipidomic analysis highlights changes in ether phospholipids and sphingomyelin. Furthermore, quantitative profiling of the SCN1A KO organoid proteome shows perturbations in cholesterol metabolism and sodium ion transportation, potentially affecting synaptic transmission. These findings suggest dysregulation of cholesterol metabolism and sodium ion transport, with implications for synaptic transmission. Overall, these insights shed light on the molecular mechanisms underlying SCN1A-associated disorders, such as Dravet syndrome, and offer potential avenues for therapeutic intervention.
本研究采用脑类器官结合多组学方法，研究1型钠通道蛋白α亚基（SCN1A）基因敲除（SCN1A KO）对大脑发育和功能的影响。通过全面的组学分析，我们发现，在无基质分化条件下，与对照组相比，SCN1A KO类器官生长减缓、神经递质水平失调，脂质组学、蛋白质组学和转录组学图谱发生改变。神经化学分析显示关键神经递质水平降低，脂质组学分析突出了醚磷脂和鞘磷脂的变化。此外，SCN1A KO类器官蛋白质组的定量分析表明胆固醇代谢和钠离子转运受到干扰，可能影响突触传递。这些发现提示胆固醇代谢和钠离子转运失调，对突触传递产生影响。总体而言，这些见解揭示了SCN1A相关疾病（如德热综合征）的分子机制，并为治疗干预提供了潜在途径。
