Bridging the gap in Parkinson's disease research: from general pathophysiology to advanced 3d cell culture models

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder, having a substantial negative impact on the quality of life of patients with its wide range of motor and non-motor symptoms. PD has a complex etiology involving aging, genetic, and environmental factors. The hallmark of the pathology in PD is the accumulation of misfolded alpha-synuclein, a presynaptic vesicle-associated protein, in dopaminergic neurons, causing neuronal death in the substantia nigra pars compacta (SNpc) and other brain regions. This review focuses on the main pathophysiological mechanisms of PD and in vitro cell culture models. Conventional 2-dimensional (2D) systems can not properly mimic living tissue and reflect disease pathology. On the other hand, 3-dimensional (3D) cell culture models bring an innovative perspective to PD research because they offer tissue-like 3D environments that support the functioning and viability of cells. The potential use of spheroids and organoid systems, 3D bio-printing, microfluidic systems, and organ-on-chip models is discussed in comparison with traditional approaches using 2D. These methods have great potential for more realistic simulation of the dynamics of the disease, allowing the investigation of therapeutic molecules and targets. This review synthesizes current knowledge on PD mechanisms and 3D in vitro models, and explains why 3D offers advantages over 2D for studying disease and testing therapies.