Abstract
Neuroinflammation is a driving force contributing to neurodegenerative diseases, including Parkinson's disease
(PD). Microglia are the primary immune cell of the brain and are among the first responders to infection, toxic
insult and aggregated proteins and contribute significantly to neuroinflammation and neurodegeneration. The
microglial inflammatory response, including inflammasome activation, has been demonstrated to be significantly
associated with PD. Paraquat (PQ) is a commonly used herbicide that has been linked to increased risk for PD.
PQ-induced neurodegeneration is tightly coupled to the activation of microglia and appears to require priming of
the microglial response. Therefore, factors that modulate the microglial inflammatory response could lead to
neuroprotection and slow the progression of neurodegenerative diseases. However, to date, no anti-
inflammatory drugs have proven successful in human clinical trials necessitating research on new targets. Hv1
(HVCN1) is a voltage-gated proton channel highly expressed on microglia in the brain and in other immune cells
in the body. This proton channel regulates the activity of NADPH oxidase and production of reactive oxygen
species in immune cells and especially microglia. Our preliminary data demonstrate that PQ directly increases
Hv1 levels in microglia, possibly through an epigenetic mechanism involving histone acetylation. Further, our
data demonstrate effects of PQ on the NLRP3 inflammasome that appear to be regulated by Hv1, providing a
potential mechanism contributing to PQ-induced microglial priming. This proposal seeks to test the hypothesis
that Hv1 regulates priming of microglia following PQ exposure through the NLRP3 inflammasome, leading to
neuroinflammation and neurodegeneration. The Specific Aims of this project are to 1) Determine mechanisms
of Hv1 regulation following paraquat exposure 2) Define the role of Hv1 in regulation of the NLRP3 inflammasome
following paraquat exposure and 3) Determine the contribution of microglial Hv1 and the NLRP3 inflammasome
in regulating neurodegeneration following paraquat exposure. Completion of these Aims will define regulatory
mechanisms for Hv1 and determine the role of Hv1 in regulation of the NLRP3 inflammasome activation and
their role in PQ-induced neuroinflammation and neurotoxicity. Together, these Aims will provide crucial
information on the function of a novel regulator of neuroinflammation, Hv1, and determine whether targeting Hv1
may be a viable therapeutic strategy in toxicant-induced neurodegeneration.
