Institute of Molecular and Cell Biology, A*STAR Research Entities, 138673, Singapore, Singapore.
School of Biological Sciences, Nanyang Technological University, 637551, Singapore, Singapore.
Cell Death Dis. 2020 Mar 13;11(3):182. doi: 10.1038/s41419-020-2383-6.
Mutations in mitochondrial DNA (mtDNA), typically maternally inherited, can result in severe neurological conditions. There is currently no cure for mitochondrial DNA diseases and treatments focus on management of the symptoms rather than correcting the defects downstream of the mtDNA mutation. Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS) is one such mitochondrial disease that affects many bodily systems, particularly the central nervous system and skeletal muscles. Given the motor deficits seen in MELAS patients, we investigate the contribution of motor neuron pathology to MELAS. Using a spinal cord organoid system derived from induced pluripotent stem cells of a MELAS patient, as well as its isogenically corrected control, we found that high levels of Notch signaling underlie neurogenesis delays and neurite outgrowth defects that are associated with MELAS neural cultures. Furthermore, we demonstrate that the gamma-secretase inhibitor DAPT can reverse these neurodevelopmental defects.
线粒体 DNA（mtDNA）突变通常呈母系遗传，可导致严重的神经疾病。目前尚无针对线粒体 DNA 疾病的治疗方法，治疗方法主要集中在管理症状，而不是纠正 mtDNA 突变下游的缺陷。线粒体脑肌病、乳酸酸中毒和卒中样发作（MELAS）就是这样一种影响许多身体系统的线粒体疾病，特别是中枢神经系统和骨骼肌。鉴于 MELAS 患者存在运动功能障碍，我们研究了运动神经元病变对 MELAS 的影响。使用源自 MELAS 患者诱导多能干细胞的脊髓类器官系统及其同基因校正对照，我们发现 Notch 信号通路的高水平是神经发生延迟和神经突生长缺陷的基础，这些缺陷与 MELAS 神经培养物有关。此外，我们证明了γ-分泌酶抑制剂 DAPT 可以逆转这些神经发育缺陷。
