Sustained proinflammatory signaling contributes to neurodegeneration in Parkinson’s disease

Current evidence suggests a causal role of inflammation in the pathogenesis of Parkinson’s Disease (PD). PD is a progressive neurodegenerative disorder that is associated with loss of dopaminergic neurons and the aberrant accumulation of alpha-synuclein fibrils called Lewy bodies (LBs) within the substantia nigra (SN) as part of its pathology. Importantly, alpha-synuclein fibrils are capable of interacting with toll-like receptor 2 (TLR2) on both neurons and microglia to induce an inflammatory response. Previous work has investigated the effects pre-existing inflammation on neurodegeneration, however the relationship between pre-existing peripheral inflammation on alpha-synuclein fibril induced brain pathology in an animal model of PD is not known. Our study thus sought to understand the downstream signaling effects of activating two known pro-inflammatory receptors TLR2 and IL-1R1 in vitro and the effects of peripheral inflammation preceding alpha-synuclein-induced PD pathology in vivo. Our preliminary studies demonstrated the expression and functionality of IL-1R1 in SH-SY5Y cells. Activation of either TLR2 by PAM3CSK4 or IL-1R1 by IL-1[beta] caused a decrease in expression of phosphorylated ERK1/2 and promoted cell death in SH-SY5Y cells. We also observed that activation of either TLR2 or IL-1RI induced an increase in IL-1RI expression in SH-SY5Y cells. Taken together, these results suggest a crosstalk between TLR2 and IL-1RI that we infer may be essential in the degeneration of the dopaminergic neurons in the SN. Moreover, prior exposure to a low dose of lipopolysaccharide (LPS) systemically increased the expression of IL-1[beta], phosphorylated-ERK1/2, and nuclear factor of kappa light polypeptide gene enhancer in B-cells, alpha (I[gamma]B[alpha]) compared to animals that received saline. Animals that received both LPS and alpha-synuclein pre-formed fibrils (PFFs) exhibited increased phosphorylated-ERK1/2 and I[gamma]B[alpha] expression compared to animals that received either LPS or PFFs only. These findings suggest crosstalk between TLR2 and IL-1R1 signaling via altered ERK1/2 and NF-[gamma]B activity, increased IL-1[beta] expression that collectively lead to exacerbation of the inflammatory response during PD pathogenesis.M.S., Pharmacology and Physiology -- Drexel University, 201