Animal models for preclinical Parkinson's research: An update and critical appraisal

Animal models of Parkinson's disease (PD) are essential to investigate pathogenic pathways at the whole-organism level. Moreover, they are necessary for a preclinical investigation of potential new therapies. Different pathological features of PD can be induced in a variety of invertebrate and vertebrate species using toxins, drugs, or genetic perturbations. Each model has a particular utility and range of applicability. Invertebrate PD models are particularly useful for high throughput-screening applications, whereas mammalian models are needed to explore complex motor and non-motor features of the human disease. Here, we provide a comprehensive review and critical appraisal of the most commonly used mammalian models of PD, which are produced in rats and mice. A substantial loss of nigrostriatal dopamine neurons is necessary for the animal to exhibit a hypokinetic motor phenotype responsive to dopaminergic agents, thus resembling clinical PD. This level of dopaminergic neurodegeneration can be induced using specific neurotoxins, environmental toxicants, or proteasome inhibitors. Alternatively, nigrostriatal dopamine degeneration can be induced via overexpression of α-synuclein using viral vectors or transgenic techniques. In addition, protein aggregation pathology can be triggered by inoculating preformed fibrils of α-synuclein in the substantia nigra or the striatum. Thanks to the conceptual and technical progress made in the past few years a vast repertoire of well-characterized animal models are currently available to address different aspects of PD in the laboratory.