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

Ria de Haas; Lisa C M W Heltzel; Denise Tax; Petra van den Broek; Hilbert Steenbreker; Michel M M Verheij; Frans G M Russel; Adam L Orr; Ken Nakamura; Jan A M Smeitink

doi:10.1093/braincomms/fcz016

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

Brain Commun. 2019;1(1):fcz016. doi: 10.1093/braincomms/fcz016. Epub 2019 Sep 13.

Authors

Affiliations

¹ Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
² Central Animal Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
³ Department of Pharmacology and Toxicology, Radboud Center for Mitochondrial Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
⁴ Department of Cognitive Neuroscience, Centre for Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
⁵ Helen and Robert Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY, USA.
⁶ Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA, USA.
⁷ Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
⁸ Khondrion BV, Nijmegen, The Netherlands.

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.

Keywords: Parkinson’s disease; animal model; dopamine; genetic model; microdialysis.

Grants and funding

R01 NS091902/NS/NINDS NIH HHS/United States