Phenotypic characterization of recessive gene knockout rat models of Parkinson's disease

Abstract

Recessively inherited loss-of-function mutations in the PTEN-induced putative kinase 1(Pink1), DJ-1 (Park7) and Parkin (Park2) genes are linked to familial cases of early-onset Parkinson's disease (PD). As part of its strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson's Research (MJFF) funded the generation of novel rat models with targeted disruption ofPink1, DJ-1 or Parkin genes and determined if the loss of these proteins would result in a progressive PD-like phenotype. Pathological, neurochemical and behavioral outcome measures were collected at 4, 6 and 8months of age in homozygous KO rats and compared to wild-type (WT) rats. Both Pink1 and DJ-1 KO rats showed progressive nigral neurodegeneration with about 50% dopaminergic cell loss observed at 8 months of age. ThePink1 KO and DJ-1 KO rats also showed a two to three fold increase in striatal dopamine and serotonin content at 8 months of age. Both Pink1 KO and DJ-1 KO rats exhibited significant motor deficits starting at 4months of age. However, Parkin KO rats displayed normal behaviors with no neurochemical or pathological changes. These results demonstrate that inactivation of the Pink1 or DJ-1 genes in the rat produces progressive neurodegeneration and early behavioral deficits, suggesting that these recessive genes may be essential for the survival of dopaminergic neurons in the substantia nigra (SN). These MJFF-generated novel rat models will assist the research community to elucidate the mechanisms by which these recessive genes produce PD pathology and potentially aid in therapeutic development.

PINK1 and Parkin: emerging themes in mitochondrial homeostasis

“…(1) The majority of studies utilise proliferating cell lines and although such systems are unrivalled for the tractable [31,32]. In contrast, Parkin KO rats do not exhibit significant PD-related pathology due to probable redundancy of E3 ubiquitin ligases, for example MUL1 [26].…”

Pathology of the Aging Brain in Domestic and Laboratory Animals, and Animal Models of Human Neurodegenerative Diseases

“…34,38,67,153 More Ab pathology in the prefrontal cortex of beagles is associated with poorer executive function. 39,67 Entorhinal Ab is correlated with poor visual learning ability. 67 Another very useful noninvasive and indirect measure of brain Ab can be by measuring the ratio of Ab42/40 in the cerebrospinal fluid (CSF), which decreases in a linear fashion with increasing amounts of Ab measured biochemically in the brain.…”

“…211 Other transgenic models such as the Park2 knockout mouse and Pink1 knockout rat develop different pathological (Table 3), neurochemical and behavioral phenotypes that are more or less comparable to human PD. 39 …”

Parkin and PINK1 functions in oxidative stress and neurodegeneration

“…Similar to Parkin knockout mice (Goldberg et al 2003), PINK1 knockout mice do not develop nigral dopamine neuron loss but exhibit mitochondrial respiration defects in the striatum but not in the cortex at 3–4 months (Kitada et al 2007; Zhou et al 2007; Gispert et al 2009; Akundi et al 2011). Multiple groups have reported significant nigral cell loss in 8–9 month old PINK1 knockout rats using rigorous stereology (Dave et al 2014; Villeneuve et al 2014). …”