Title: Single-cell transcriptomics revealed molecular vulnerability in human midbrain-like organoid model of Parkinson's Disease.
Presenter: Huck Hui NG
Affiliation: Professor. Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore.
Date: July 11, 2025, 5pm
Place: Seminar room 316, Building 4, RCAST
Abstract:
Organoid, such as the human midbrain-like organoid (hMLO), presents a renewable and
experimentally tractable platform to investigate pathophysiology of Parkinson's Disease.
However, the utility of hMLO is still limited by our incomplete understanding of its biology.
Here, we performed in-depth transcriptomic characterization of human pluripotent stem
cell-derived hMLO at late stage, up to day 150 in vitro, with single-cell and spatial resolution.
We identified distinct physiological neural cell types that showed high molecular similarity
to fetal midbrain cell classes, relevance to PD risk genes, and spatial distribution reminiscent
of their relative in vivo anatomy. Additionally, we found hMLO DaN subtypes delineated
along the established developmental axis of SOX6 and CALB1. Interestingly, we found
enrichment of differential biological processes in each subtype, suggesting their
fundamental differences in vulnerability in PD that seems to be encoded early in
development. Leveraging the hMLO model to investigate the effect of a PD-related
mutation DJ-1, we found that DJ-1–deficient hMLOs spontaneously recapitulate PD
pathophysiology of a-synuclein aggregations, Lewy-body-like inclusions and midbrain DaN
neurodegeneration. Single-cell transcriptomic analysis revealed both shared and unique
molecular perturbances resulting from DJ-1 loss in all hMLO cell types and DaN subtypes.
Taken together, this study establishes and enhances the suitability of hMLOs as a useful
human-based physiological model to enable better understanding of PD pathogenesis and
therapeutic development.