Identifying Factors That Modulate Neuronal Subtype Vulnerability To Lewy Pathology

Intracellular inclusions containing the protein α-synuclein (α-syn), known as Lewy pathology (LP), characterize the age-related neurodegenerative disorders termed synucleinopathies, the most prevalent being Parkinson’s disease (PD). The motor and non-motor symptoms that define PD correlate closely with neuronal dysfunction and/or loss in select brain regions such as the hippocampus and the dopaminergic neurons of the substantia nigra pars compacta (SNpc). Genetic evidence indicates that perturbations in α-syn are causative for PD, and data from histopathology, cellular, and animal models suggest that LP transmits between brain regions. How LP affects stereotypical neuronal populations and is associated with selective neuronal toxicity has been difficult to study because the majority of disease models do not recapitulate both features. I therefore used a novel mouse model where recombinant α-syn is misfolded in vitro into pre-formed fibrils (PFFs) and used to initiate the formation of Lewy-like pathology and neuronal loss. In this thesis, I first reviewed the evidence relating to α-syn pathological spreading, neuronal vulnerability, and neurotoxicity. One mechanism of vulnerability that emerged from my research is that hippocampal CA2-3 neurons are selectively vulnerable to PFF-induced toxicity relative to neighboring neurons due to their higher α-syn protein levels. Neuronal viability could be rescued by reducing α-syn expression but only within a short window after pathology formation, suggesting a toxic threshold in these neurons. However, toxicity could still be attenuated at later time points with antioxidants acting through a glutathione-dependent mechanism. Another key finding is that mice lacking a functional adaptive immune system (AIS) show no detectable alterations in α-syn accumulation, SNpc neuron loss, or motor phenotype after intracerebral PFF-injection. In the process of demonstrating that the AIS is not necessary for these processes, I identified a mouse strain with known innate immune system dysfunction that exhibited a potentiated phenotype. Taken together, these results suggest that both cell-autonomous and non-autonomous factors help determine neuronal vulnerability and contribute to neurodegeneration in synucleinopathies