Modelling Parkinson's Disease: iPSCs towards Better Understanding of Human Pathology

Abstract

Parkinson's Disease (PD) is a chronic neurodegenerative disorder characterized by motor and non-motor symptoms, among which are bradykinesia, rigidity, tremor as well as mental symptoms such as dementia. The underlying cause of Parkinson disease is degeneration of dopaminergic neurons. It has been challenging to develop an efficient animal model to accurately represent the complex phenotypes found with PD. However, it has become possible to recapitulate the myriad of phenotypes underlying the PD pathology by using human induced pluripotent stem cell (iPSC) technology. Patient-specific iPSC-derived dopaminergic neurons are available and present an opportunity to study many aspects of the PD phenotypes in a dish. In this review, we report the available data on iPSC-derived neurons derived from PD patients with identified gene mutations. Specifically, we will report on the key phenotypes of the generated iPSC-derived neurons from PD patients with different genetic background. Furthermore, we discuss the relationship these cellular phenotypes have to PD pathology and future challenges and prospects for iPSC modelling and understanding of the pathogenesis of PD.

Keywords: Parkinson’s disease; human pathology; induced pluripotent stem cells.

Figure 1

Parkinson’s disease (PD) modelling. PD have been modelled and studied using post-mortem (A) tissues derived from PD. (B) Animal models have been vastly used both by knocking down specific gene or with use of chemicals. This help researchers to investigate the associated phenotypes such as mitochondrial dysfunction, neuronal degeneration and protein folding and aggregation for creating an efficient animal model and use in drug discovery and toxicity. (C) Novel induced pluripotent stem cells have been derived from somatic cells of a PD or a healthy individual, leading to generate a disease model in a dish where different phenotypes can be investigated and pave the way towards drug discovery, toxicity testing and cell therapy interventions.

Figure 2

Induced pluripotent stem cell (iPSC)-derived dopaminergic neurons modelling the role of mutant SNCA. The illustration shows the impact of the mutated α-synuclein in different cellular processes within the cell.

Figure 3

Effect of PINK1 and parkin mutation in IPSC-derived neurons. Parkin mutation in iPSC-derived neurons showed impairment in their requitement to PINK1, alteration in spontaneous postsynaptic current activity, reduction in dopamine receptor and release. PINK1 mutation in iPSC-derived neurons displayed fragmented mitochondria with alteration their DNA level, ATP, membrane potential and oxidative stress. Additionally, there is an increase in apoptotic cell death and α-synuclein aggregation and accumulation.

Figure 4

Pathways of mitochondrial dysfunction, a major cellular and clinical phenotype in PD. Mitochondrial dysfunction can result from impairment in mitochondrial fission, change in mitochondrial morphology, electron transport chain, increase in mtDNA, elevation in oxidative stress leading to reactive oxygen species generation, alteration in mitochondrial biogenesis and electron transport dysfunction. These can lead and associated with protein aggregation and eventual endoplasmic (ER) stress that ultimately results in degeneration of dopaminergic neurons that underlines the PD pathogenesis.