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

Abstract

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., 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, in their analysis, the authors excluded an important alternative perspective that Parkinson disease encompasses many other underlying mechanisms and deficits in addition to nigrostriatal dopamine depletion. Here, based on data from our laboratory and others, we propose that the Pink1 / genetic model is useful for studying signs and non-dopaminergic pathology, especially in this specific genetic rat model. Assessing if a model is useful based only on nigrostriatal dopamine mechanisms and associated behaviours ignores many other crucial aspects of Parkinson disease (discussed below) and can have serious negative consequences on advancing research and treatment approaches. Parkinson disease has a complex pathology that is not well-understood. Parkinson disease is a progressive degenerative disorder that affects nearly 10 million people worldwide (1–2% of the population), and its incidence is expected to increase as the current population ages. It is commonly characterized and diagnosed by the following four major clinical signs: Bradykinesia, rigidity, tremors and postural instability. These motor signs are attributed to the substantial loss of the neurotransmitter dopamine. However, in most cases, neuron dysfunction and cell death (including outside the dopaminergic system) precede presentation of motor signs, likely manifesting at least a decade before a clinical diagnosis. Moreover, the mechanisms by which this occurs are currently unknown. Parkinson disease encompasses pathology beyond nigrostriatal dopamine depletion. Parkinson disease pathology occurs at multiple levels throughout the central nervous system, including the lower brainstem, and affects multiple neurotransmitters and pathways. Additionally, current research has expanded our knowledge of underlying pathology to peripheral systems. For example, current hypotheses have focussed on the ascending spread of protein pathology (mainly aggregated a-synuclein) from the gut (via the vagus nerve) to the caudal brainstem. This is consistent with Braak central nervous system staging of Parkinson disease, where central nervous system pathology ascends in a caudal to rostral fashion as the disease progresses. Thus, earlystage (Braak Stage 1) Parkinson disease pathology is concentrated in brainstem regions such as the dorsal motor nucleus of the vagus nerve, anterior olfactory structures, and in Braak Stage 2 lower raphe nuclei and the locus coeruleus. This correlates with deficits in the noradrenergic system and early onset behavioural changes in vocalization, olfaction and attention. The substantia nigra is likely then impacted in Braak Stage 3; typically, this corresponds to the onset of the classical Parkinson disease motor signs and a clinical diagnosis. Again, this is consistent, as reviewed by Schapira et al., with the working hypothesis that Parkinson disease likely manifests years