Cellular models for Parkinson's disease

Abstract

Developing new therapeutic strategies for Parkinson's disease requires cellular models. Current models reproduce the two most salient changes found in the brains of patients with Parkinson's disease: The degeneration of dopaminergic neurons and the existence of protein aggregates consisting mainly of a-synuclein. Cultured cells offer many advantages over studying Parkinson's disease directly in patients or in animal models. At the same time, the choice of a specific cellular model entails the requirement to focus on one aspect of the disease while ignoring others. This article is intended for researchers planning to use cellular models for their studies. It describes for commonly used cell types the aspects of Parkinson's disease they model along with technical advantages and disadvantages. It might also be helpful for researchers from other fields consulting literature on cellular models of Parkinson's disease. Important models for the study of dopaminergic neuron degeneration include Lund human mesencephalic cells and primary neurons, and a case is made for the use of nondopaminergic cells to model pathogenesis of non-motor symptoms of Parkinson's disease. With regard to a-synuclein aggregates, this article describes strategies to induce and measure aggregates with a focus on fluorescent techniques. Keywords: Dementia with Lewy bodies, FRET, non-motor symptoms.This article is part of a special issue on Parkinson disease. General remarks about models for Parkinson's diseaseParkinson's disease (PD) is a common neurodegenerative disease. Life expectancy is reduced in PD patients (Macleod et al. 2014), and there is currently no causal treatment option. Developing a new therapeutic strategy requires understanding the pathogenesis of the disease and testing interventions that could have beneficial effects. Both require models, since the use of PD patients is limited by heterogeneity of disease burden, slow progression, technical obstacles and of course ethical considerations. Current models of PD only partially reproduce the disease for two main reasons. First, we do not know what causes sporadic PD and therefore cannot reproduce the entire pathogenesis in a model. Second, we want a model that unlike PD itself develops pathology quickly and reliably. In addition, we want to be able to monitor and manipulate the model easily, and test many approaches simultaneously. For these reasons, a useful model needs to differ from PD in critical aspects. Models can represent aspects of PD found on the level of behaviour, electrical activity, individual cells and/or molecules. The choice of model will depend on the aspect of the disease we want to study and the kind of therapy we want to develop. If we want to develop a medication, it will have a molecular target thus a cellular model can be a good starting point.As compared to animal models, cellular models develop pathology more quickly, are less costly and do not require ethical approval. Genetic or pharmacological manipulations and time-lapse imaging are easier and m...

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