Study Rationale:
In Parkinson’s disease (PD), it is clear that the alpha-synuclein protein accumulates in specific neurons, thereby damaging them to cause neurological symptoms. Remarkably, misfolded forms of this alpha-synuclein protein spread from one cell to another through the fluid spaces of the brain. Understanding how this extracellular alpha-synuclein is either removed from the brain or delivered to neurons to exert its toxic actions is central to defining PD progression and will provide opportunities to modify disease course.
Hypothesis:
We hypothesize that PD initiation and progression depends on the balance of extracellular alpha-synuclein aggregate clearance between beneficial removal from the brain via VEGF-dependent meningeal lymphatics versus deleterious uptake into neurons via mGlu4 receptors.
Study Design:
We will enhance meningeal lymphatic clearance with a lymphatic-specific VEGF-C variant and suppress clearance with a VEGFR-3 decoy in mouse PD models to determine the role of this pathway in removal of extracellular alpha-synuclein seeds from the brain. We will define the molecular mechanisms of neuronal mGlu4-mediated uptake of extracellular alpha-synuclein leading to neurodegeneration in mouse PD models, including an assessment of mGlu4 interaction with mGlu7 genetic risk of PD and methods for mGlu4 pharmacological regulation. Our studies will utilize traditional mouse models of recombinant synuclein injection or transgenic overexpression, while also developing a more translationally relevant method for infusion of human disease CSF into mice.
Impact on Diagnosis/Treatment of Parkinson’s disease:
Pharmacological targeting of neuronal mGlu4-mediated uptake may slow, halt or prevent the ability of extracellular brain alpha-synuclein to drive PD, while promoting lymphatic VEGF-C-mediated elimination from the brain may remove the culprit. Together, the two approaches provide a comprehensive approach to rebalance clearance and achieve disease modification by limiting neuronal uptake of alpha-synuclein and enhancing extracerebral removal of alpha-synuclein fibrils.
Next Steps for Development:
Pharmacological targeting of mGlu4-mediated neuronal uptake of alpha-synuclein may achieve beneficial disease modification in PD via orally available CNS-penetrant allosteric modulators. VEGF-C-based biological agents may achieve enhanced lymphatic clearance and favorably modify PD course disease without CNS delivery. Combining these approaches is likely to synergistically enhance therapeutic benefit.