University of Luxembourg, Esch-sur-Alzette, Luxembourg
Abstract
Affecting over 10 million people worldwide, Parkinson’s disease is the second most common neurodegenerative disorder. With only 10% of cases having a known genetic cause, PD aetiology largely remains an enigma. Endogenous factors such as genetic predisposition, and exogenous factors such as exposure to toxins and lifestyle choices, interplay in the initiation and acceleration of the disease. Despite some common hallmarks such as nigrostriatal degeneration and Lewy bodies pathology, PD clinical picture largely varies across patients. Non-motor symptoms are common and thought to emerge up to 20 years prior to diagnosis, and they range from gastro-intestinal dysfunction to sleep disturbances to hallucinations. 90% of PD patients present at least one neuropsychiatric symptom, and about 30% of total patients develop dementia. Interventions aimed to prevent or slowdown disease progression require a better understanding of the early molecular events which foster neuronal dysfunction and death. Longitudinal studies which allow the investigation of early pathological stages are challenging to achieve on patients-based study only, thus largely rely on the use of animal models. Specifically, rodents have very similar anatomy, physiology, and genetics to humans, and a good set of genetic/molecular tools are available to generate pathological models. In the present thesis, we ventured into the investigation of alpha-synuclein dependent and independent models of PD, to unravel the early molecular events driving PD pathogenesis.
Firstly, we investigated a genetic mouse model overexpressing the human, E46K mutated alpha-synuclein gene. We characterised neurodegeneration in the nigrostriatal pathway and motor deficits, detecting characteristics of an early-PD phenotype. Aiming to understand the molecular events driving neurodegeneration, we profiled the ventral midbrain transcriptome at different ages, uncovering that transcriptional changes are an early response to the alpha-synuclein challenge. Being the E46K mutation associated with dementia, we also profiled the hippocampus to investigate early transcriptional events linked with cognitive dysfunction in PD. We revealed that hippocampal dysfunction is mostly driven by the ageing process, operating over the interplay of genetic and gender predisposition.
Secondly, we profiled transcriptomic changes in the midbrain of the alpha-synuclein independent, Park7-/- (DJ-1 KO) mouse model. Once again, we uncovered the interplay of sex and age in determining the susceptibility to the disease challenge, with males being more affected than females. Specifically, the response to DJ-1 loss of function appeared to be largely sex-specific, and to be mediated by the oestrogen pathway and the DJ-1/Nrf2/CYP1B1 axis. Even if sex-dimorphism has not been directly investigated in human Park7 PD cases due to their paucity, it has been reported in sporadic PD for several populations. Thus, our findings might significantly contribute to uncovering the reasons behind gender differences in PD.
Thirdly, we investigated a moderate overexpressor of wild-type alpha-synuclein (Thy1-Syn14), aiming to reach a compromise between genetic and idiopathic PD modelling. To understand how endogenous and exogenous factors interplay in disease onset and progression, we exposed transgenic mice to the amyloidogenic protein Curli and to a fibre deprived diet. We uncovered that microbiome insults and diet act in combination to promote disease progression, and we provided supporting evidence to the concept of a gut-brain axis in PD. Our results underline the relevance of lifestyle adjustments in the management of PD patients.
Finally, we investigated how different alpha-synuclein moieties and glutamate exposure might contribute to neurodegeneration. Even if these studies were left incomplete, we gained some preliminary indications which can represent a starting point for future research. We observed that both oligomers and fibrils are toxic forms of alpha-synuclein, and that a lack of standardisation in recombinant moieties production is a current issue that may halt reproducibility in alpha-synuclein research. We also reported a higher susceptibility of DJ-1 knock-down cells to glutamate excitotoxicity, potentially underlying an additional mechanism through which DJ-1 loss of function is responsible for PD development