New Developments in Genetic rat models of Parkinson's Disease

Abstract

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.

Sphingosine-1-Phosphate Receptors Modulators Decrease Signs of Neuroinflammation and Prevent Parkinson’s Disease Symptoms in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model

“…disease as complex as PD, it would still be interesting to verify whether FTY720 and SEW2871 provide also protection during the formation of a-synuclein aggregates that resemble Lewy bodies or Lewy neurites. For instance, chronic administration of neurotoxins induces progressive PD rodent models that include a-synuclein aggregates in addition to motor deficits and rapid nigrostriatal dopaminergic cell death (Creed and Golberg, 2018). Furthermore, genetic-based approaches including transgenic models, viral vector-mediated models based on genes linked to monogenic PD as well as introduction of a-synuclein preformed fibrils all induce toxic protein aggregates in rodents.…”

Analysis of α-Synuclein Pathology in PINK1 Knockout Rat Brains

“…Subsequent studies of the same line of PINK1-/- rats reported mitochondrial dysfunction, behavioral deficits, loss of neurons in the substantia nigra and locus coeruleus, neurochemical abnormalities and α-synuclein aggregates in various brain regions (Grant et al, 2015; Kelm-Nelson et al, 2015, 2016, 2018; Pultorak et al, 2016; Stauch et al, 2016a,b; Villeneuve et al, 2016a,b). We sought to further characterize PINK1-/- rats specifically with respect to α-synuclein pathology because spontaneous formation of α-synuclein aggregates (without α-synuclein overexpression or injection) is a rare and important feature of PD animal models and because α-synuclein aggregation has been implicated both genetically and biochemically as a mechanism of PD pathogenesis as well as a potential therapeutic target (Goldberg and Lansbury, 2000; Creed and Goldberg, 2018).…”

Genomics of Speech and Language Disorders

“…PINK1 is a gene involved on early-onset PD. Pink1-KO rats have mitochondrial abnormalities, and proteinase K-resistant aSyn aggregates in different brain regions [40,41] . Additionally, rats exhibit significant vocalization deficits dependent on age, intensity, bandwidth, and peak frequency [39] .…”