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Transgenic Overexpression of GPNMB Protects Against MPTP‐Induced Neurodegeneration

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease worldwide behind Alzheimer's disease. One feature of PD is the marked loss of dopaminergic neurons leading to diminished release of dopamine into the basal ganglia, leading to motor dysfunction. Diminished dopamine release manifests as the hallmark symptoms of Parkinson's disease: resting tremor, rigidity, bradykinesia, and akinesia. Currently, there are no therapies to effectively slow disease progression, thus, novel drug discovery is of paramount importance. GPNMB is a transmembrane glycoprotein, with reported anti‐inflammatory, reparative, and neuroprotective functions. GPNMB has reported neuroprotective functions in mouse models of cerebral ischemia/reperfusion and amyotrophic lateral sclerosis (ALS). Here, we aimed to investigate GPNMB's neuroprotective ability in an acute 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease. For this investigation we utilized 10–12‐week‐old male transgenic mouse overexpressing GPNMB (GPNMB‐TG) and age‐matched male C57 Black/6N wild‐type mice. Control mice were injected with saline, while MPTP‐treated mice were treated with 15 mg/kg of MPTP. Mice were injected every two hours, a total of four times and sacrificed one week after the last injection, and midbrain and striatum were collected for HPLC, western blot, and histological analyses. An additional study followed the same paradigm, but mice were sacrificed two days after the final injection in order to assess the effects of GPNMB overexpression on inflammation. Western blot analysis of the striatum revealed a significantly elevated level of tyrosine hydroxylase and dopamine active transporter in GPNMB‐TG MPTP‐treated mice compared to C57 MPTP‐treated mice. Additionally, MPTP‐induced neuron loss was attenuated in GPNMB‐TG mice compared to wild‐type mice. Furthermore, we have shown that GPNMB‐TG MPTP‐treated mice have reduced gliosis and inflammation compared to wild‐type MPTP‐treated mice. This indicates that GPNMB may play a role in microglia and led us to investigate this role. We show that recombinant GPNMB (rGPNMB) reduces the inflammatory response in primary microglia cultures following lipopolysaccharide (LPS) treatment. Specifically, rGPNMB significantly reduces the gene expression of pro‐inflammatory cytokines and rescues the loss of anti‐inflammatory gene expression following LPS treatment. Furthermore, rGPNMB reduces nitric oxide production following LPS treatment in primary microglia. Taken together, these results suggest that GPNMB is neuroprotective in the acute MPTP mouse model of PD by acting as an anti‐inflammatory agent. The mechanism by which GPNMB inhibits inflammation in microglia is currently being investigated by our laboratory.