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Targeting the Voltage-Gated Proton Channel Hv1 for Neuroprotection

The goal of this project is to validate the voltage-gated proton channel Hv1 as a target to reduce neuroinflammation and subsequent neurodegeneration in acute and chronic pre-clinical models of Parkinson’s disease (PD).

Project Description:             
The voltage-gated proton channel Hv1 is required for activation of enzymes that contribute to neuroinflammation, and recently, pre-clinical models lacking Hv1 were found to be protected from neuroinflammation and cell death in a stroke model. In this project, researchers will determine whether models lacking Hv1 are protected from the dopaminergic neurotoxicity of PD.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
Targeting of neuroinflammation in PD pre-clinical models and in clinical trials has met with mixed results. One potential reason is that the targets of these drugs are not unique to microglia: immune cells that contribute significantly to neuroinflammation. Thus, validation of cell-specific regulators of neuroinflammation, such as Hv1, would represent a significant advance in targeting the neuroinflammation that occurs in PD.

Anticipated Outcome:
Successful completion of this project will serve as proof-of-concept that Hv1 is a viable target in PD. Hv1 is a particularly attractive target since it appears to be restricted to microglial cells in the brain. Thus, chemical screening for Hv1 antagonists would be the next step to identify small-molecule drugs that could be incorporated into the models established in this grant.

Progress Report

To date we have characterized the presence of the proton channel HV1 in activated microglia, the resident
immune cells of the brain. Further, pre-clinical models lacking Hv1 appear to demonstrate less neuroinflammation than models with Hv1. Because neuroinflammation is an important mediator of dopamine neuron death in Parkinson's disease, these results suggest that Hv1 may be a viable target to reduce neurodegeneration.

November 2014

Final Outcome

Hv1, a tiny pore on the surface of some cells, is required for the development of inflammation. Hv1 is present in microglia, the cells responsible for brain inflammation in PD. A PD-inducing chemical MPTP caused significantly less brain damage in pre-clinical models lacking Hv1. The lack of Hv1 in these models either prevented the production of inflammation-inducing molecules, such as tumor necrosis factor, or reduced their levels. Similar results were obtained in another model of Parkinson's with inflammation-induced nerve cell death. Taken together, these data suggest that Hv1 regulates brain inflammation and represents a novel target for therapies protecting dopamine-producing nerve cells.

October 2016

Presentations & Publications
Manuscripts describing this work are in their final stages of preparation. There is an initial paper describing the LPS model and then 1-2 additional manuscripts describing the HVl work.


  • Jason R. Richardson, PhD, MS, DABT

    Rootstown, OH United States

  • Long-Jun Wu, PhD

    Piscataway, NJ United States

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