Alpha synuclein functions as a sex-specific modulator of cognition and gene expression

Abstract

Neurodegenerative diseases such as Alzheimer’s and Parkinson’s impact large portions of the population. Though such diseases have distinguishing features, they also often share pathology and symptomology. Alpha synuclein (αSyn; gene SNCA) is a protein commonly found in a range of neurodegenerative conditions. αSyn can interact with tau and amyloid-beta to modulate disease phenotypes, but its normal functions remain incompletely characterized. To explore the contribution of αSyn to Alzheimer’s disease, I first asked whether reducing αSyn in a mouse model of Alzheimer’s would improve cognition. Using a translationally relevant strategy, the reduction of αSyn reveled a sex-specific effect whereby male, but not female, mice showed improved spatial memory. Follow-up studies with constitutive SNCA knockout mice revealed a previously unreported female-specific deficit in spatial learning and memory. Next, we utilized electrophysiology, immunofluorescence imaging and transcriptomics to elucidate potential mechanisms underlying this effect. Results revealed a novel impairment in long-term potentiation, as well as differential expression of genes related to learning and immune function in female mice in response to SNCA ablation. These results not only describe a novel sex-specific function of αSyn, but provide translationally-relevant information regarding the potential effects of using αSyn reduction as a therapeutic strategy for neurodegenerative conditions.