On the implementation of single-cell omics and CRISPR screens for iPSC-models of Parkinson’s disease

Parkinson’s disease (PD) is currently the fastest growing neurological condition, with an urgent need for effective treatments to slow or stop disease progression. The advent of induced pluripotent stem cells (iPSC) models has significantly enhanced our understanding of PD by providing unprecedented access to disease-relevant cell types. These PD in vitro models have provided novels insights into mitochondrial dysfunction, lysosomal and autophagic dysregulation, protein aggregation, stress response, inflammation and metabolic perturbations. However, cellular heterogeneity and variability across iPSC lines are inherent limitations of these models which are often overlooked. Here we discuss ongoing efforts and opportunities to improve PD models by incorporating recent advancements in single-cell multi-omics analyses. We also highlight the lack of genetic CRISPR screens using iPSC-models of PD and discuss current limitations and prospects. We argue that implementing and combining these tools has the potential to unlock novel insights into the pathological mechanisms of PD that could lead to new therapeutic targets for this devastating disorder.