Recessively inherited loss-of-function mutations in the Parkin, DJ-1 or PINK1 gene are linked to familial cases of early-onset Parkinson’s disease (PD). Single knockout (KO) mice (lacking either Parkin, DJ-1 or PINK1) and triple-knockout (lacking all three genes) exhibit disruptions of dopamine homeostasis but no dopaminergic degeneration in the substantia nigra (SN). As part of the strategy to provide more tools for the research community, The Michael J. Fox Foundation for Parkinson’s Research (MJFF) has funded the generation of novel rat models lacking either Parkin, DJ-1 or PINK1 genes. Additionally, MJFF sponsored a standardized characterization including behavioral, neurochemical and pathological measures to determine if these rats exhibit progressive PD-like phenotype. The PINK1 KO rats demonstrated motor dysfunction and gait impairment compared to wild-type rats (WT), and some of these deficits were progressive starting as early as 8-weeks of age and continuing up to 8-months of age. These deficits included increased hind-limb foot slips in the tapered beam test, decreased rearing in fatigue challenge test, loss of hind-limb grip strength, impaired mobility in the open-field, gait disturbances in the Neurocube, lack of hind-limb extensor strength, decreased air-righting reflex and reduced muscle tone. The DJ-1 KO rats expressed similar motor and gait abnormalities, however these deficits were less pronounced and appeared mostly between 6 and 8 months of age. At 8-months of age, both PINK1 KO and DJ-1 KO rats showed a significant two-three fold increase in both striatal dopamine and serotonin content compared to WT, however, there were no robust differences in DOPAC, HVA and 5-HIAA levels. Moreover, stereological estimation in both PINK1 KO and DJ-1 KO rats showed a progressive loss of TH-positive neurons of the pars compacta of SN with 50% loss observed at 8-months of age compared to WT. There were no significant differences observed in the Parkin KO rats compared to WT in behavior, striatal neurotransmitter content or numbers of SN dopaminergic neurons up to 12-months of age. Characterization of alpha-synuclein immunoreactivity in these rat models is currently ongoing. These results demonstrate that loss of either the PINK1 or the DJ-1 gene in the rat produces a progressive loss of dopaminergic neurons, and that this neurodegeneration may be correlated to progressive motor and gait deficits. Thus, these MJFF-generated PINK1 and DJ-1 KO rats will help elucidate the mechanisms by which these recessive genes produce PD pathology and aid in therapeutic development.
Authors: Kuldip D. Dave, Shehan De Silva, Sylvie Ramboz, Melissa J. Beck, Changyu Quang, Stanley A. Benkovic, S. Omar Ahmad, Susan Sunkin, Dan Walker, Kevin Gamber, Yasmin Aziz, Marco A. Baptista, Sonal S. Das, Audrey Dufour, Jamie L. Eberling, Maurizio F. Facheris, Niketa Sheth, Alison Urkowitz, Brian K. Fiske, Todd B. Sherer and Mark Frasier