Toll-like Receptor Inhibition to Block Alpha-synuclein-induced Pro-inflammatory Signaling and Cytokine Release

Study Rationale:
Synucleinopathies, including Parkinson's disease (PD), are a family of central nervous system (CNS) degenerative disorders characterized by alpha-synuclein protein-containing aggregates. Toll-like receptors (TLRs), which includes TLR2, play a critical role in the immune system's response to foreign pathogens that can trigger adverse inflammatory signaling. Recently, alpha-synuclein aggregates have been shown to activate adverse inflammation signaling in the CNS. Blocking TLR2 signaling reduced this adverse inflammation signaling, suggesting alpha-synuclein aggregates activate the immune system to increase adverse inflammation signaling. Thus, TLR2 inhibition may be a therapeutic strategy to disrupt alpha-synuclein-mediated CNS inflammation and slow PD progression.

Hypothesis:
Small molecule inhibition of TLR2 signaling is a disease-modifying strategy for reducing alpha-synuclein-mediated CNS inflammation.

Study Design:
Using both human immune cell lines, we will confirm that alpha-synuclein activates TLR2 to stimulate inflammation signaling. We will design and develop small molecules that inhibit TLR2 signaling and reduce downstream inflammation signaling. We will measure this effect by analzying release of pro-inflammatory molecules (cytokines). We will optimize the lead molecules to make them suitable for proof-of-concept studies in pre-clinical models.

Impact on Diagnosis/Treatment of Parkinson's Disease:
Inhibition of a TLR2-mediated adverse inflammation signaling cascade may serve as a novel therapeutic strategy for slowing PD progression. The data generated from this project will provide a clear go/no-go decision regarding the viability of this approach.

Next Steps for Development:
We will conduct pharmacokinetic (PK)/pharmacodynamic (PD)/time course analyses to understand TLR2 inhibition efficacy in alpha-synuclein transgenic models. We will use these PK/PD data to build a translational biomarker platform strategy for TLR2 inhibition in the CNS. Early biomarker inclusion in discovery will facilitate confirmation of mechanism of action and target engagement to aid clinical hypothesis testing.