From Gut to Brain - αSynuclein pathology spreading in a new transgenic mouse model

Abstract

Age-related neurodegenerative disorders such as Parkinson’s disease (PD) represent a challenge to contemporary society. The increase in life expectancy and the lack of therapies addressing the disease cause make these disorders a high burden to patients, caretakers and society in general. Aggregation of αSynuclein (αSyn) and presence of characteristic motor symptoms are cardinal features of PD. The onset of PD motor symptoms is however preceded by non-motor symptoms that can start decades earlier. These may be associated with initiation of αSyn pathology in the peripheral nervous system, more precisely in the enteric nervous system (ENS) and/or olfactory system. Several studies have been performed in patients as well as in animal models to investigate the spreading of αSyn from the periphery to the central nervous system (CNS). Animal models of αSyn gut-to-brain spreading are usually based on the injection of αSyn aggregates or on viral overexpression of αSyn, with both cases implying external manipulation. Hence, the main aim of this thesis was to characterise a novel, non-invasive, transgenic mouse model of spontaneous αSyn gut-to-brain spreading.This mouse model, named Vitras, expresses aggregation prone human 1-120αSyn exclusively in the gut in a αSyn-null background. To determine whether the presence of human or mouse αSyn in the background could affect the spreading of αSyn, two additional versions of the Vitras line, expressing either endogenous mouse αSyn (Vitras6J) or full-length human αSyn (VitrasBAC), were characterised. We found that gut-to-brain αSyn spreading can occur independently from the presence of endogenous full-length αSyn and was present at 3 months of age. The first gut-derived αSyn-positive neurons in the brain were detected in the dorsal motor nucleus of the vagus nerve, followed by other brainstem nuclei. In addition to the brain, gut-derived αSyn was also found in the spinal cord, lungs and heart. Although none of the mouse lines presented constipation, Vitras mice developed a hyperactive behaviour at 12 months of age. To understand the mechanisms of αSyn spreading at a cellular level, a neuronal co-culture system of ENS-CNS neurons was set up. Moreover, in an attempt to identify compounds to target αSyn aggregation a new oligomer-modulator, Sery315b, was tested in various cellular models. Due to time limitations these studies were not completed. In conclusion, the work demonstrated that the Vitras models are valuable tools to investigate the mechanisms of αSyn pathology spreading from the ENS to the CNS and to test possible therapies aimed at slowing down disease progression in PD.