Sex and LRRK2 Genotype Differences in Inflammation and Dopaminergic Neurodegeneration in a Multi-Hit Model of Parkinson's Disease

Abstract

Parkinson's disease (PD) is a multifactorial condition arising from a constellation of environmental insults in conjunction with genetic vulnerabilities, sex differences, and aging. The objective of the current thesis was to explicate potential additive/synergistic effects of genetic LRRK2 anomalies and environmental risk factors as they pertain to motor behaviour, nigrostriatal dopaminergic degeneration, and indices of neuroinflammation. Moreover, since the male sex represents a significant risk factor in PD, sexual dimorphisms were addressed. To achieve this, male and female mice bearing the G2019S-LRRK2 mutation were exposed to a systemic lipopolysaccharide (LPS) + paraquat (PQ) neurotoxicant challenge. Contrary to expectations, no additive/synergistic effects were observed between the G2019S mutation and LPS+PQ exposure. In fact, male G2019S mice appeared to be protected from the degenerative effects of LPS+PQ at this age. Moreover, an unanticipated sex by treatment interaction was found, such that female mice displayed greater deficits in gait and greater loss in nigral TH-positive neurons compared to males. SEX AND LRRK2 GENOTYPE DIFFERENCES IN PDiii Acknowledgements