One Step Into the Future: New iPSC Tools to Advance Research in Parkinson's Disease and Neurological Disorders

Abstract

Studying Parkinson's disease (PD) in the laboratory presents many challenges, the main one being the limited availability of human cells and tissue from affected individuals. As PD is characterized by a loss of dopaminergic (DA) neurons in the brain, it is nearly impossible for researchers to access and extract these cells from living patients. Thus, in the past PD research has focused on the use of patients' post-mortem tissues, animal models, or immortalized cell lines to dissect cellular pathways of interest. While these strategies deepened our knowledge of pathological mechanisms in PD, they failed to faithfully capture key mechanisms at play in the human brain. The emergence of induced pluripotent stem cell (iPSC) technology is revolutionizing PD research, as it allows for the differentiation and growth of human DA neurons in vitro, holding immense potential not only for modelling PD, but also for identifying novel therapies. However, to reproduce the complexity of the brain's environment, researchers are recognizing the need to further develop and refine iPSC-based tools. In this review, we provide an overview of different systems now available for the study of PD, with a particular emphasis on the potential and limitations of iPSC as research tools to generate more relevant models of PD pathophysiology and advance the drug discovery process.

Keywords: CRISPR; Parkinson’s disease; Stem cells; cell therapy; co-cultures; neuronal organoids.

Fig.1

The iPSC toolbox. Representation of the multiple tools available for creating in vitro models using iPSC. The upper left panel represents genome-editing techniques that allowing for the creation of isogenic pairs of stem cell lines. Clockwise, the other panels depict models of increasing complexity such as co-cultures, 3D organoids and assembly of multiple organoids on a chip. The main strengths and limitations of the different models are highlighted in the adjacent squares.