Modelling Parkinson’s Disease Pre-Clinically: A Novel Virus-Fibril Inducible Mouse Model Exploring Disease Characteristics and Therapeutic Intervention via Metabotropic Glutamate Receptor 5 Negative Allosteric Modulation

Abstract

The objective of this thesis was two-fold: first, to develop and characterize a novel Parkinson's disease (PD) mouse model, and second, to assess the therapeutic potential of a metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulator (NAM). Using viral overexpression of α-synuclein in combination with the addition of exogenous synthetic α-synuclein pre-formed fibrils (PFFs), we demonstrate that the double-hit virus-fibril model can consistently induce motor impairments and α-synuclein spread in male mice. Remarkably, we observed motor impairment in the absence of degeneration, suggesting that perhaps α-synuclein induces biochemical changes in the motor cortex that translate to behavioural impairment. Secondly, we also demonstrate that treatment with the mGluR5 NAM, (2-chloro-4-[2[2,5-dimethyl-1-[4-(trifluoromethoxy) phenyl] imidazol-4-yl] ethynyl] pyridine (CTEP), prevented the onset of and improved existing motor impairments, α-synuclein burden, along with altering S6 ribosomal (rS6) protein activity. Finally, we observed a robust sex difference, that clearly favored motor pathology in males. In fact, males displayed motor impairment after 8-16-weeks, whereas females show no motor impairment whatsoever (even after many months). Yet, it was surprising that there were no clear pathological differences between the sexes that could possibly explain the differences observed in motor behaviour. Taken together, the data presented in this thesis offers insight into the role of α-synuclein in the development of PD and offers support for mGluR5 NAMs as potential disease altering therapeutic for PD, with the obvious caveat being that dramatic sex-differences were evident for the behavioral outcomes.