The genetic dissection of trisomy 21 and partial trisomy 21 cellular pathologies using induced pluripotent stem cells

• Main Author: Gough, Gillian
• Other Authors: Foo Jia Nee
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2021
• Subjects: Science::Medicine
• Online Access: https://hdl.handle.net/10356/153265
• Institution: Nanyang Technological University

Introduction: Down Syndrome (DS), caused by full or partial trisomy of chromosome 21 (T21 or pT21) presents with accelerated ageing, intellectual disability (ID) and Alzheimer’s disease (AD). The contributions of individual HSA21 gene overdoses to these features remain poorly understood. Methods: iPSCs were generated from two individuals with pT21 and were utilised in combination with an already published isogenic model of DS . Isogenic iPSCs were generated by CRISPR/Cas9 genome modification of candidate HSA21 genes (APP, BACE2, DYRK1A and SOD1) or stable integration of fluorescent bio-sensors. Results: (i)We generated the first human isogenic model of the partial trisomy of the DS critical region (DSCR). (ii)The T21-caused cellular phenotypes of increased accumulation of mitochondrial H2O2, and DNA double-strand break repair foci, are visible in undifferentiated pluripotent hiPSCs; (iii)BACE2 is a dose-dependent repressor of AD-like pathology in cerebral organoids.