Modeling Parkinson's disease‐related symptoms in alpha‐synuclein overexpressing mice

Background: Intracellular deposition of alpha-synuclein (alpha-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. Transgenic mouse models overexpressing human alpha-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop alpha-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of alpha-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions. Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies. Methods: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) alpha-syn in the context of their validity and utility for different types of behavioral studies. Conclusions: By applying appropriate behavioral tests, alpha-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other alpha-synucleinopathies.