Mimicking Parkinson’s Disease in a Dish: Merits and Pitfalls of the Most Commonly used Dopaminergic In Vitro Models

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder and has both unknown etiology and non-curative therapeutic options. Patients begin to present the classic motor symptoms of PD-tremor at rest, bradykinesia and rigidity-once 50-70% of the dopaminergic neurons of the nigrostriatal pathway have degenerated. As a consequence of this, it is difficult to investigate the early-stage events of disease pathogenesis. In vitro experimental models are used extensively in PD research because they present a controlled environment that enables the direct investigation of the early molecular mechanisms that are potentially involved with dopaminergic degeneration, as well as for the screening of potential therapeutic drugs. However, the establishment of PD in vitro models is a controversial issue for neuroscience research not only because it is challenging to mimic, in isolated cell systems, the physiological neuronal environment, but also the pathophysiological conditions experienced by human dopaminergic cells in vivo during the progression of the disease. Since no previous work has attempted to systematically review the literature regarding the establishment of an optimal in vitro model, and/or the features presented by available models used in the PD field, this review aims to summarize the merits and limitations of the most widely used dopaminergic in vitro models in PD research, which may help the PD researcher to choose the most appropriate model for studies directed at the elucidation of the early-stage molecular events underlying PD onset and progression.

Back and to the Future: From Neurotoxin‐Induced to Human Parkinson's Disease Models

“…However, while being simplified, in vitro cellular models offer advantages in speed, cost, ease of manipulation, and decreased animal use (Kepp, Galluzzi, Lipinski, Yuan, & Kroemer, 2011). Cellular models are ideally suited for the investigation of intracellular mechanisms underlying pathological conditions and screening of protective compounds (Falkenburger, Saridaki, & Dinter, 2016;Kepp et al, 2011;Lopes, Bristot, da Motta, Parsons, & Klamt, 2017). Moreover, with current advances in automated microscopy and the advent of machine learning-based image analysis, in vitro cellular models are becoming capable of delivering multimodal data at an unprecedented scale (Boutros, Heigwer, & Laufer, 2015).…”

In vitro Models of Neurodegenerative Diseases

“…Human neuroblastoma cells Differentiate into neuronal-like cells exhibiting cholinergic, dopaminergic, or noradrenergic phenotypes (Lopes et al, 2017) Neuroblastoma origin may influence differentiation, viability, growth performance, metabolic properties and genomic stability. Multiple differentiation protocols lead to different outcomes (Xicoy et al, 2017).…”

“…Similar proliferation rate to human neurons. Suitable for the generation of genetic models (Lopes et al, 2017).…”

“…Dissection procedure can introduce experimental variability (Xicoy et al, 2017). Species-dependent differences (Lopes et al, 2017).…”

Age-dependent neuroprotective effect of an SK3 channel agonist on excitotoxity to dopaminergic neurons in organotypic culture

“…However, primary cultures are limited in their viability in vitro and only allow observation of short-term effects of toxicity [26]. Organotypic cultures retain some of the 3D shape and some modicum of connections with normal anatomical targets, and most importantly, can be maintained in culture for much longer periods of time [26]. This report describes age-dependent susceptibility to excitotoxity of dopaminergic neurons in organotypic culture, as well as the impact of neuroprotection by an SK3 agonist, 1-EBIO, in organotypic cultures of different ages.…”