- 學位論文
探討自閉症類群之運動神經元缺失
Modeling Motor Neuron Deficits in Autism Spectrum Disorder
摘要
動作發展是探索世界及主動社交互動的第一步，而運動缺陷常見於泛自閉症類群 (Autism spectrum disorder, ASD)中，且和ASD之核心症狀像是在社交能力以及人際溝通上的障礙有關聯，故運動神經元缺陷可能和ASD之致病機制相關。此研究利用患有ASD和Phelan-McDermid syndrome (PMS) 所建立的誘導型多能性幹細胞 (human induced pluripotent stem cells, hiPSC)分化成人類運動神經元作為細胞模式，提供此疾病一新穎的觀點。 利用帶有SHANK3基因缺陷之PMS-iPSC，我們獲得高純度的PMS患者的運動神經元，並發現運動神經元之產率不會受到疾病影響，但PMS患者的運動神經元之粒線體有氧氣消耗速率降低的現象。此外，ASD患者特有的拷貝數變異 (copy number variation, CNV) 包含對於基因造成複寫 (duplication) 或缺失 (deletion)，在ASD患者周邊血液所建立的細胞株 (lymphoblastoid cell lines, LCLs) 中發現到基因表現量的改變，其中，SND1、 ABAT、 SLC38A10以及 RAB39B 之表現量上升，而 HDAC4、GNB1L、RPL10之表現量下降。 總結本研究，ASD特有的CNV在ASD的病因中扮演重要的角色，且運動神經元中的粒線體缺失可能與PMS以及ASD患者之運動缺失之致病機制有關聯，提供ASD之基礎或臨床研究不同的觀點。
並列摘要
Autism spectrum disorder (ASD) presents motor deficits, which are related to core symptoms, impairments in social interaction and communication, suggesting motor neuron deficits may contribute to the etiology of ASD. Here, we proposed a novel point of view on ASD by using PMS-iPSC-derived motor neurons as an in vitro model. Using PMS-iPSC harboring SHANK3 deletion, we obtained high-purity PMS-MNs and found that the PMS-MN generation was not altered. However, PMS-MNs had reduced oxygen consumption rate (OCR). In addition, we identified ASD-specific copy number variations (CNVs) and found CNVs, including duplication and deletion, of genes, influenced the expression level of genes in ASD-derived lymphoblastoid cell lines (LCLs) such as increased expression of SND1, ABAT, SLC38A1 and RAB39B and decreased expression of HDAC4, GNB1L, and RPL10. Combining results presented in this thesis, our data suggest that case-specific CNVs may play an essential role in the pathogenesis of ASD. Mitochondrial dysfunction may be a potential mechanistic link between motor deficits and contribute to core symptoms of PMS and ASD, which provided further insights into basic and clinical researches of ASD.