Early ?-Synuclein Pathology Induces Neuroinflammation and Decreases Topoisomerase II? Expression in A53T Mice

Abstract

Neuroinflammation in the pathogenesis of neurodegenerative diseases is still a subject of discussion, as it might be either the cause or the result of neurodegeneration. Misfolded or improperly aggregated alpha-synuclein in Parkinson's Disease, can cause inflammatory responses, indicating a mechanistic relationship between alpha-synuclein pathology and neuroinflammation. The aim of this study was to investigate the role of DNA topoisomerase II beta, the key player of DNA topology, in the neuroinflammation process in an age-dependent transgenic Parkinson's Disease mouse model overexpressing the A53T mutant alpha-synuclein. In this study, transgenic and control mice were bred in three age groups as early (3 months), mid (8 months), and late (12 months) disease stages. Behavioral experiments were carried out to compare the age-related cognitive and motor coordination functions. Cytokine levels in the serum and protein expression levels in the dissected brain were analyzed by both western blot and immunofluorescence staining. A decline was observed in the cognitive and motor coordination functions depending on age. Disease-related markers at protein level appeared even in the early stage, and accordingly, a significant increase was observed in inflammatory markers and cytokine levels compared to control. DNA Topoisomerase II beta and Nurr1 levels decreased in transgenic mice, especially more dramatically in the early stage. The combined effect of reduced Nurr1 and DNA Topoisomerase II beta, along with increased inflammation, may provide a better understanding of the pathogenesis of Parkinson's Disease at early-stage and requires for further investigation of the potential alterations in topo II beta as an intervention strategy for this disease.