Microglial innate and adaptive immune function modulates disease pathology in and environmental pesticide model of Parkinson's disease

Abstract

Parkinson's Disease (PD) is the world's foremost movement disorder with pathological features including loss of dopaminergic neurons (DAn) within the substantia nigra pars compacta (SNpc), chronic activation of glial cells, and the misfolding and aggregation of a-synuclein (a-syn). Compounding evidence gathered over the past two centuries suggests environmental exposures, genetics, and aging can induce complicated cell-to-cell interactions that evoke and facilitate chronic inflammatory states; but the role that individual glial cells, in particular microglia, have in the progression of disease remains unknown. Difficulties in recapitulating the three pathological hallmarks of PD underscore the need for better animal models. To address this gap in functional investigation, the studies herein provide, for the first time, an optimized environmental exposure model with the pesticide rotenone (2.5mg/kg/day) in murine, which has proven effective at mirroring DAn degeneration, gliosis and misfolded a-syn accumulation. The pathology observed was region-, time- and dose-dependent, emphasizing the importance of environmental exposure and associated PD diagnosis. The successful optimization of this exposure model has allowed for its implementation in transgenic mice, which was previously unfeasible. To determine microglial specific innate inflammatory reactions in the progression of PD, we targeted the inflammatory transcriptional regulator NF-kB by use of transgenic CX3CR1-Cre