Animal models of Parkinson's disease: bridging the gap between disease hallmarks and research questions

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor and non-motor symptoms. More than 200 years after its first clinical description, PD remains a serious affliction that affects a growing proportion of the population. Prevailing treatments only alleviate symptoms; there is still neither a cure that targets the neurodegenerative processes nor therapies that modify the course of the disease. Over the past decades, several animal models have been developed to study PD. Although no model precisely recapitulates the pathology, they still provide valuable information that contributes to our understanding of the disease and the limitations of our treatment options. This review comprehensively summarizes the different animal models available for Parkinson's research, with a focus on those induced by drugs, neurotoxins, pesticides, genetic alterations, α-synuclein inoculation, and viral vector injections. We highlight their characteristics and ability to reproduce PD-like phenotypes. It is essential to realize that the strengths and weaknesses of each model and the induction technique at our disposal are determined by the research question being asked. Our review, therefore, seeks to better aid researchers by ensuring a concrete discernment of classical and novel animal models in PD research.

Keywords: Alpha-synuclein; Animal model; Mouse; Parkinson’s disease; Preformed fibril; Transgenic model.

Fig. 1

The hallmarks of Parkinson’s disease (PD). Predominant PD motor symptoms arise from DA neuron loss in the SNpc, and the denervation of their axons in the caudate nucleus and putamen, also called the striatum. The cause of PD remains unclear but involves loss of DA neurons, α-syn aggregation, mitochondrial dysfunction, autophagy impairments, and neuroinflammation. PD patients additionally exhibit non-motor symptoms. The figure was generated using BioRender.

Fig. 2

Schematic summary of the current known mechanisms that trigger DA neuron death, and the action of different genes and compounds used to model PD. The loss of DA neurons could result from impaired protein degradation, mitochondrial dysfunction, α-syn aggregation, and neuroinflammation, which can be induced by neurotoxic or genetic alteration. The reduced DA signaling through drug inhibition could also lead to a PD-like phenotype. LPS: lipopolysaccharide, DAT: dopamine transporter, VMAT: vesicular monoamine transporter, NM: neuromelanin, DA: dopamine. The figure was generated using BioRender.