To be or not to be pink(1): contradictory findings in an animal model for Parkinson’s disease

Abstract

The PTEN-induced putative kinase 1 knockout rat (Pink1−/−) is marketed as an established model for Parkinson’s disease, characterized by development of motor deficits and progressive degeneration of half the dopaminergic neurons in the substantia nigra pars compacta by 8 months of age. In this study, we address our concerns about the reproducibility of the Pink1−/− rat model. We evaluated behavioural function, number of substantia nigra dopaminergic neurons and extracellular striatal dopamine concentrations by in vivo microdialysis. Strikingly, we and others failed to observe any loss of dopaminergic neurons in 8-month-old male Pink1−/− rats. To understand this variability, we compared key experimental parameters from the different studies and provide explanations for contradictory findings. Although Pink1−/− rats developed behavioural deficits, these could not be attributed to nigrostriatal degeneration as there was no loss of dopaminergic neurons in the substantia nigra and no changes in neurotransmitter levels in the striatum. To maximize the benefit of Parkinson’s disease research and limit the unnecessary use of laboratory animals, it is essential that the research community is aware of the limits of this animal model. Additional research is needed to identify reasons for inconsistency between Pink1−/− rat colonies and why degeneration in the substantia nigra is not consistent.

Pink1−/− rats are a useful tool to study early Parkinson disease

“…The Pink1 −/− rat model does have limitations, including less dopamine depletion than is seen in humans, hindlimb issues which may be an unknown consequence of the genetic mutation, and less behavioural robustness than the mouse model. As clearly described in de Haas et al 1 , there have been studies by several groups, including ours, that have failed to replicate findings of consistent limb motor changes by 8 months of age with severity of nigrostriatal dopamine depletion. We agree with de Haas et al 1 that there is a lack of reproducibility of the original 25–50% reduction reported by Dave et al 11 Additional explanation for the discrepancies, not addressed in the paper, may include experimental controls such as light cycle, age and use of rat breeding lines, as well as social enrichment variables, especially with frequent behavioural testing.…”

“…As clearly described in de Haas et al 1 , there have been studies by several groups, including ours, that have failed to replicate findings of consistent limb motor changes by 8 months of age with severity of nigrostriatal dopamine depletion. We agree with de Haas et al 1 that there is a lack of reproducibility of the original 25–50% reduction reported by Dave et al 11 Additional explanation for the discrepancies, not addressed in the paper, may include experimental controls such as light cycle, age and use of rat breeding lines, as well as social enrichment variables, especially with frequent behavioural testing. In fact, we found that when we do not assay multiple behaviours every 1–2 months, behavioural deficits and brain neurochemistry is different than in animals that receive consistent conspecific and experimenter/handler interactions.…”

“…These signs are clinically identical to those of individuals with sporadic forms of the disease. Similarly, the Pink1 −/− rat model demonstrates early motor and non-motor deficits and, as discussed in de Haas et al, 1 mild nigrostriatal dopamine loss at 8–10 months of age, providing a parallel link between the model and human Parkinson disease. Further, the 25–50% range of reported nigral dopamine loss in the Pink1 −/− rat model is consistent with Braak early-stage pathology.…”

“…In the 2019 publication ‘To be or not to be pink (1): contradictory findings in an animal model for Parkinson disease’ by de Haas et al, 1 the authors presented important data with regard to the discrepancies in the number of substantia nigra dopamine neurons and extracellular striatal dopamine concentrations reported by their laboratory and others in the Pink1 −/− rat model of Parkinson disease. We agree with the data and the interpretation of the data with regard to this aspect of Parkinson disease.…”

“…However, at the behavioural level, Pink1 −/− rats tend to mimic the human symptomatology showing motor and also non-motor and non-classical motor impairments. As de Haas et al 1 conclude, the Pink1 −/− may not be the best model to study certain mid to late-stage characteristics of Parkinson disease, such as nigrostriatal dopamine depletion. However, our research demonstrates that the Pink1 −/− rat a valid model for testing a wide range of prodromal, early and progressive sensorimotor deficits including vocalization, tongue function (strength), chewing, swallowing, gait, spontaneous movement, fine motor control, anxiety, anhedonia, cognition and nociception as well as relevant underlying pathology such as noradrenergic dysfunction.…”