Modeling Cell-Cell Interactions in Parkinson's Disease Using Human Stem Cell-Based Models.

Katrin Simmnacher,Johanna Kaindl,Tania Rizo,Jonas Lanfer,Beate Winner

doi:10.3389/fncel.2019.00571

Katrin Simmnacher, Johanna Kaindl + Show 3 more

Open Access

https://doi.org/10.3389/fncel.2019.00571

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Abstract

Parkinson’s disease (PD) is the most frequently occurring movement disorder, with an increasing incidence due to an aging population. For many years, the post-mortem brain was regarded as the gold standard for the analysis of the human pathology of this disease. However, modern stem cell technologies, including the analysis of patient-specific neurons and glial cells, have opened up new avenues for dissecting the pathologic mechanisms of PD. Most data on morphological changes, such as cell death or changes in neurite complexity, or functional deficits were acquired in 2D and few in 3D models. This review will examine the prerequisites for human disease modeling in PD, covering the generation of midbrain neurons, 3D organoid midbrain models, the selection of controls including genetically engineered lines, and the study of cell-cell interactions. We will present major disease phenotypes in human in vitro models of PD, focusing on those phenotypes that have been detected in genetic and sporadic PD models. An additional point covered in this review will be the use of induced pluripotent stem cell (iPSC)-derived technologies to model cell-cell interactions in PD.

Highlights

PARKINSON’S DISEASEParkinson’s disease (PD) is the second most frequently occurring neurodegenerative disorder
Neuropathological hallmarks of PD include the selective loss of midbrain dopaminergic neurons in the pars compacta of the substantia nigra (SNpc), and the presence of α-synuclein-protein (α-Syn) in intracytoplasmic and intraneuritic eosinophilic inclusions, termed Lewy bodies and Lewy neurites, respectively (Pakkenberg et al, 1991; Braak and Braak, 2000)
The majority of research has focused on familial PD, despite the fact that this constitutes less than 10% of all PD cases

Summary

INTRODUCTION

Parkinson’s disease (PD) is the second most frequently occurring neurodegenerative disorder. Human stem cell-based disease modeling provides a means of studying both genetic and sporadic PD and of testing for suitable compounds that may target the neurodegenerative process in PD (Marchetto et al, 2010; Durnaoglu et al, 2011). The patterning of organoid differentiation toward distinct brain-region specific fates, including midbrain-like organoids containing DA neurons, is of particular relevance in terms of PD (Qian et al, 2016; Smits et al, 2019) Despite this astonishing progress, disease modeling using human stem cells is still accompanied by a number of caveats. Extremely productive efforts by the stem cell field in recent years have greatly expanded the toolbox available for PD disease modeling (see Figure 1) This toolbox has been essential in identifying pathological phenotypes in human stem cell models of familial and sporadic PD. We will provide an overview of the major phenotypes that were recently identified

Neurite Defects

Cell Death

Findings

Stressor Response