A Novel Parkinson’s Disease Model: PINK1/PARKIN Double‐Knockout Rats

Abstract

IntroductionAnimals are important tools to study pathological changes, behavioral abnormalities, and therapeutics in Parkinson’s disease (PD), which is characterized by loss of dopaminergic neurons in the substantia nigra (SN). Loss‐of‐function mutations in PTEN‐induced putative kinase 1 (PINK1) and Parkin, mitophagy pathway genes are linked to autosomal recessive PD in humans; however, deficiency does not lead to PD symptoms or affect dopaminergic neurons in the SN in mice. In rats, loss of PINK1, but not Parkin, leads to progressive neurodegeneration in the SN and motor symptoms in a subset of animals. To try to obtain a more robust model of PD, we generated a PINK1/Parkin double‐knockout (PP‐DKO) rat model.HypothesisWe hypothesized that PP‐DKO have mitochondrial dysfunction leading to a loss in dopaminergic neurons in the SN causing motor deficits.MethodsUsing PP‐DKO rat model, mitochondrial bioenergetics were measured by seahorse‐XF96, neuronal quantification by immunohistochemistry and stereology, and behavioral assessment examining motor coordination, bradykinesia/agility, hindlimb strength, and gait.ResultsStriatal mitochondrial bioenergetics displayed dysfunction at 3‐month old rats. Maximal respiration and spare respiratory capacity were decreased. PP‐DKO at 6 and 8 months showed a 23% and 45% reduction in dopaminergic neurons in the SN; respectively. Also, a 30% reduction in the number of neurons was found in the ventral tegmental area at the 8 months. Motor coordination was assessed by rotarod, which showed a reduction in the latency to fall at 6‐ and 9‐months old rats. Bradykinesia and agility were tested by pole test that showed an increase in the time the rat required to turn and to walk down the pole at 6‐ and 9‐months old rats. Cylinder test showed a significant reduction in hindlimb strength when rearing frequency was measured at 6, and 8 months of age. Finally, gait abnormalities were also present at 8 months including reduction in hindlimb step length, reduction in fore‐ and hindlimb step pressure alongside with an increase in step angle.ConclusionPP‐DKO is a novel genetic model with reproducible neuropathology and motor abnormalities of PD that will help researchers to study the mechanisms by which recessive genes produce PD as well as testing preventative and potential therapeutic paradigms.Support or Funding InformationThis research was funded by Michael J. Fox Foundation for Parkinson’s research grant #15288