Development and Characterisation of a Rat Model of Parkinson's Disease

Abstract: Preclinical rodent models of Parkinson’s Disease (PD) based on alpha-synuclein (αSyn) present some of the pathological hallmarks of the human condition, such as the progressive loss of dopaminergic neurons in the substantia nigra (SN) and the development of behavioural deficits. However, numerous reports on these models highlighted the variable outcomes that might originate from them if not validated properly. This thesis seeks to develop and characterise a rat model of PD, which present stable and relevant pathology and to be utilised for the investigation of disease progression and the assessment of therapeutic interventions. At first, we compared different αSyn models based on the injection of an adeno-associated virus (AAV) overexpressing human αSyn and/or the inoculation of preformed fibrils (PFFs). Although some additional pathology (i.e. increased protein aggregation and inflammation) could be obtained by combining AAV-αSyn and PFFs, AAV-αSyn alone was sufficient to generate a model that would present neuronal loss, Lewy-like pathology, and behavioural impairments. We, therefore, further investigated the ability of AAV-αSyn to model early stages of PD. We could detect a progressive development of motor and cognitive symptoms by using simple drug-free behavioural tests and concomitant neuronal loss in the SN. Subsequently, we demonstrated, for the first time in an AAV-αSyn model, attentional neglect, as well as deficits in movement initiation and movement completion using a lateralised choice reaction time task. Eventually, we tested whether our newly characterised model could be useful in the assessment of disease-modifying therapies, such as the injection of neurotrophic factors. We, therefore, tested the potential beneficial effects of a new candidate among them, the growth differentiation factor 5 (GDF5). Unfortunately, the injection of AAV-GDF5 did not exert any neuroprotective effect in our model. Taken together, these results show that it was possible to replicate our AAV- αSyn rat model between studies, and it presents stable neurodegeneration, synucleinopathy, as well as motor and cognitive deficits which can be assessed by a wide battery of simple and complex behavioural tests.