A Novel Neuroprotective Effect of Osteoactivin in Parkinson's Disease

Parkinson's disease is the second most prevalent neurodegenerative disease worldwide, and is caused by a significant loss of dopaminergic neurons in the substantia nigra pars compacta in the midbrain. Dopaminergic cell death leads to decreased release of dopamine into the basal ganglia motor pathway. 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. Osteoactivin (OA), a transmembrane protein discovered in the osteopetrotic rat model, may have anti‐inflammatory and reparative functions. OA has recently shown neuroprotective ability in mouse models of cerebral ischemia/reperfusion and amyotrophic lateral sclerosis (ALS). In the ALS study, transgenic mice overexpressing OA were bred with the SOD1 G93A mice (ALS model) mice. These mice had less skeletal muscle atrophy, and a less severe phenotype compared to SOD1 G93A mice. Additionally, intramuscular injection of OA improved the phenotype in SOD1 G93A mice. For the cerebral ischemia reperfusion model, OA transgenic mice had superior blood flow and smaller infarct size compared to control mice. In this study, we first examined the expression of OA in post‐mortem brain tissue from human Parkinson's patients and found that OA mRNA expression was significantly down regulated compared to the non‐Parkinson's brains. Next, we aimed to investigate OA's neuroprotective ability in the 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model of Parkinson's disease. For this investigation we utilized (n=10) 10–11 month old male transgenic mouse overexpressing OA (OA‐TG) and ten age matched C57/Black/6 wild‐type mice. Five wild‐type mice and five OA‐TG mice were injected with saline (control), while five wild‐type and five OA‐TG mice were injected with 10 mg/kg of MPTP. Mice were injected every two hours, a total of four times. Mice were then sacrificed one week after the last injection, and midbrain and striatum were collected for HPLC, western blot, and histological analyses. High performance liquid chromatography (HPLC) analysis showed a significant increase in the levels of dopamine and 3,4‐dihydroxyphenylacetic acid (DOPAC), a metabolite of dopamine, in the striatum of OA‐TG MPTP treated mice compared to MPTP treated wild‐type mice. Additionally, HPLC showed elevated levels of Homovanillic acid (HVA), another metabolite of dopamine. Western blot analysis of the striatum revealed a slightly elevated level of tyrosine hydroxylase and dopamine active transporter. Taken together, these results indicate that overexpression of OA may provide a neuroprotective response. Studies are underway to evaluate the dopaminergic neurons in the substantia nigra to determine whether OA provides a neuroprotective function in Parkinson's disease. Future studies are directed to determine the mechanism by which OA mediates neuroprotective effects. Support or Funding Information Ohio Department of Development