Towards physiologically relevant human pluripotent stem cell (hPSC) models of Parkinson's disease

The derivation of human embryonic stem cells followed by the discovery of induced pluripotent stem cells and leaps in genome editing approaches have continuously fueled enthusiasm for the development of new models of neurodegenerative diseases such as Parkinson's disease (PD). PD is characterized by the relative selective loss of dopaminergic neurons (DNs) in specific areas of substantia nigra pars compacta (SNpc). While degeneration in late stages can be widespread, there is stereotypic early degeneration of these uniquely vulnerable neurons. Various causes of selective vulnerability have been investigated but much remains unclear. Most studies have sought to identify cell autonomous properties of the most vulnerable neurons. However, recent findings from genetic studies and model systems have added to our understanding of non-cell autonomous contributions including regional-specific neuro-immune interactions with astrocytes, resident or damage-activated microglia, neuro-glia cell metabolic interactions, involvement of endothelial cells, and damage to the vascular system. All of these contribute to specific vulnerability and, along with aging and environmental factors, might be integrated in a complex stressor-threshold model of neurodegeneration. In this forward-looking review, we synthesize recent advances in the field of PD modeling using human pluripotent stem cells, with an emphasis on organoid and complex co-culture models of the nigrostriatal niche, with emerging CRISPR applications to edit or perturb expression of causal PD genes and associated risk factors, such as GBA, to understand the impact of these genes on relevant phenotypes.

Automated summary

Research on Parkinson's disease has focused on the selective loss of dopaminergic neurons, with recent studies exploring both cell autonomous properties and non-cell autonomous contributions to the vulnerability of these neurons. These factors, including neuro-immune interactions, metabolic interactions, and damage to the vascular system, may collectively contribute to the specific vulnerability of these neurons and form a complex stressor-threshold model of neurodegeneration. Advances in modeling PD using human pluripotent stem cells, organoids, and CRISPR applications to edit PD genes aim to further understand the impact of genetic and environmental factors on the disease.