Voltage-Gated Proton Channel Hv1 Regulates Neuroinflammation and Dopaminergic Neurodegeneration in Parkinson's Disease Models.

Although the precise mechanisms for neurodegeneration in Parkinson's disease (PD) are unknown, evidence suggests that neuroinflammation is a critical factor in the pathogenic process. Here, we sought to determine whether the voltage-gated proton channel, Hv1 (HVCN1), which is expressed in microglia and regulates NADPH oxidase, is associated with dopaminergic neurodegeneration. We utilized data mining to evaluate the mRNA expression of in the brains of PD patients and controls and uncovered increased expression of the gene encoding Hv1, in the brains of PD patients compared to controls, specifically in male PD patients.

Pharmacological inhibition of CSF1R by GW2580 reduces microglial proliferation and is protective against neuroinflammation and dopaminergic neurodegeneration.

Increased pro-inflammatory cytokine levels and proliferation of activated microglia have been found in Parkinson's disease (PD) patients and animal models of PD, suggesting that targeting of the microglial inflammatory response may result in neuroprotection in PD. Microglial proliferation is regulated by many factors, but colony stimulating factor-1 receptor (CSF1R) has emerged as a primary factor. Using data mining techniques on existing microarray data, we found that mRNA expression of the CSF1R ligand, CSF-1, is increased in the brain of PD patients compared to controls.

The glycoprotein GPNMB attenuates astrocyte inflammatory responses through the CD44 receptor.

Background: Neuroinflammation is one of the hallmarks of neurodegenerative diseases, such as Parkinson's disease (PD). Activation of glial cells, including microglia and astrocytes, is a characteristic of the inflammatory response. Glycoprotein non-metastatic melanoma protein B (GPNMB) is a transmembrane glycoprotein that releases a soluble signaling peptide when cleaved by ADAM10 or other extracellular proteases.