Gavin Fuchs

Although ɑ-synuclein (ɑSyn) was originally discovered in the synapse and nucleus of neurons, where it plays a role in vesicle trafficking and synaptic plasticity, it is also expressed in the microglia of the brain. However, ɑSyn’s role in microglia, which are the primary, resident immune cells of the central nervous system, remains unclear. Due to its affinity for lipids, which are known to accumulate in some of the microglia that are associated with neurodegenerative diseases, ɑSyn may be of relevance to the pathophysiology of those neurodegenerative diseases. For example, ɑSyn knockout had a sex-dependent effect on the cognition of male and female mice, making it worse in females. To explain this sex-dependent effect, a transcriptomic analysis was completed by the Lesné lab, which identified numerous differentially expressed gene networks related to microglia, suggesting that they are displaying a unique transcriptomic and phenotypic profile. As such, it is hypothesized that ɑSyn moderates microglial morphology and function within mice in a sex-dependent manner. Specifically, it is expected that ɑSyn ablation will cause a distinct transcriptomic profile in male and female mice, corresponding with enhanced ramification and surveillance in the former. Due to their enhanced vigilance, it is predicted that ɑSyn-null female mice will experience less severe neuroinflammation in response to injection of bacterial lipopolysaccharide, a widely-used method to cause systemic inflammation and microglial activation in the brain.