Investigating neurodevelopmental defects in metabolic disease MELAS using 3D organoid model

• Main Author: Winanto
• Other Authors: Ng Shi Yan
• Format: Final Year Project
• Language: English
• Published: 2018
• Subjects: DRNTU::Science::Biological sciences::Molecular biology
• Online Access: http://hdl.handle.net/10356/74682
• Institution: Nanyang Technological University

Mitochondrial encaphalomyopathy, lactic acidosis, and stroke like episodes (MELAS) syndrome is a disorder caused by mutation in mitochondria DNA. MELAS syndrome is characterized by a myriad of multi-organs symptoms such as seizures, vomiting, muscle weakness and diabetes. One of the most causal genetic mutations of MELAS is the m.A3243G mutation that occurs in MT-TL1 gene encoding the mitochondrial tRNALeu(UUR) affecting mitochondrial protein synthesis and ultimately oxidative phosphorylation. We hypothesize that MELAS iPSCs could not develop into fully functional neurons. Motor function is also severely compromised in MELAS patients. Therefore, we sought to investigate the ability of MELAS iPSCs to differentiate into motor neuron progenitors and subsequently into neurons. Our findings suggest that MELAS iPSCs do not show defects in neural specification pathway. However, further differentiation of MELAS NPCs into 3D spinal organoids revealed a severe neurogenesis defect. We also tested the possibility of neural organoid screening by performing small molecule treatment in organoids. Lastly, we report that treatment with a gamma-secretase inhibitor could reverse the neurogenesis defects in MELAS organoids.