Seminar: "Midbrain organoids as a model to study neurodegenerative disease by investigation of gene-to-phenotype links" by Dr. Junghyun Jo

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease which is characterized by selective loss of midbrain dopaminergic (mDA) neurons in the substantia nigra pars compacta. To understand PD pathophysiology, the disease-relevant cell types, mDA neurons, are differentiated from human pluripotent stem cells (hPSCs) and are subjected to various experimental manipulations to uncover PD phenotypes and mechanisms in vitro. Although 2D differentiation models involve singular cell types in isolation has advantages for answering certain questions, it limited synaptic connectivity and cross-talk between specific cell types, which is not reflective of the complex progression of PD involving multiple cell types in the midbrain. Given this limitation of studying PD, I established a new protocol to generate 3D human midbrain-like organoids (hMLO) from hPSCs which consists of multiple cell types which are present in the human brain and recapitulate the 3D cytoarchitecture of the developing midbrain.

More recently, I am trying human-specific PD modeling using hMLOs derived from hPSCs carrying the CRISPR-mediated GBA1 knock-out (KO), one of the major risk factor for PD, as an investigation of gene-to-phenotype link at molecular and cellular level. Intriguingly, the GBA1 KO hMLOs recapitulate the pathophysiological signatures of PD with massive accumulation of glucosylceramides and led to aggregate α-synuclein and formation of Lewy body-like inclusions alongside mDA neuronal loss.

Collectively, this advanced experimental in vitro PD modeling system represents a potentially useful tool to demonstrate PD specific phenotypes and could be a versatile platform to understand pathophysiological mechanisms of PD, and thus the hMLO derived from hESCs bearing PD-associated genetic mutations or patient-derived iPSC would fulfill a need for both basic research and industrial toxicology and drug screening.

Biography

Junghyun Jo began his Ph.D. under the supervision of Prof. Dong Ryul Lee at CHA University in Seoul, Korea. He majored in Biomedical Science and studied numerous developmental biology related subjects such as germ cell biology, reproductive physiology, embryology, and stem cell biology. He is interest in somatic cell reprogramming through a direct protein introduction system to produce new iPSC lines that can be clinically applicable. He joined Genome Institute of Singapore as Postdoctoral Fellow in lab of Prof. Huck-Hui Ng and he is currently Research Associate. He conceived a new protocol to generate human midbrain-like organoids from human pluripotent stem cells that recapitulate features of the midbrain by 3D culture system to establish advanced experimental in vitro Parkinson’s disease modeling system. He is now focusing on elucidating the mechanism of neurodegeneration by investigation of pathogenesis using the isogenic human pluripotent stem cells established by CRISPR/Cas9-mediated genome engineering.