New Developments in Genetic rat models of Parkinson's Disease

Preclinical research on Parkinson's disease has relied heavily on mouse and rat animal models. Initially, PD animal models were generated primarily by chemical neurotoxins that induce acute loss of dopaminergic neurons in the substantia nigra. On the discovery of genetic mutations causally linked to PD, mice were used more than rats to generate laboratory animals bearing PD-linked mutations because mutagenesis was more difficult in rats. Recent advances in technology for mammalian genome engineering and optimization of viral expression vectors have increased the use of genetic rat models of PD. Emerging research tools include "knockout" rats with disruption of genes in which mutations have been causally linked to PD, including LRRK2, α-synuclein, Parkin, PINK1, and DJ-1. Rats have also been increasingly used for transgenic and viral-mediated overexpression of genes relevant to PD, particularly α-synuclein. It may not be realistic to obtain a single animal model that completely reproduces every feature of a human disease as complex as PD. Nevertheless, compared with mice with the same mutations, many genetic rat animal models of PD better reproduce key aspects of PD including progressive loss of dopaminergic neurons in the substantia nigra, locomotor behavior deficits, and age-dependent formation of abnormal α-synuclein protein aggregates. Here we briefly review new developments in genetic rat models of PD that may have greater potential for identifying underlying mechanisms, for discovering novel therapeutic targets, and for developing greatly needed treatments to slow or halt disease progression. © 2018 International Parkinson and Movement Disorder Society.