L‐Plastin, a Novel Regulator of Microglial Activation in Parkinson’s disease

Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease worldwide behind Alzheimer’s disease. One prominent feature of PD is the marked loss of dopaminergic and motor dysfunction. Currently, there are no therapies to effectively slow disease progression. Neuroinflammation is a major contributing factor in neurodegeneration diseases including PD. Microglia, a type of glial cell, are primary regulators of neuroinflammation and these cells are capable of assuming activation states ranging from inflammatory to anti‐inflammatory and reparative. Thus methods to combat microglial inflammation or promote microglial anti‐inflammatory and reparative effects show promise as treatments to slow neurodegeneration. L‐plastin (LPL) is an acting bundling protein and other research has shown that LPL plays a role in osteoclast function, T‐cell activation, and it may be involved in the NLRP3 inflammasome activation in macrophages. It has been shown in osteoclasts, that LPL phosphorylation at serine 5 plays a role in sealing zone formation. Using a peptide inhibitor to block phosphorylation of serine 5 on LPL prevented sealing zone formation and inhibited osteoclast‐mediated bone resorption. Given the evidence that LPL may play a role in inflammasome activation in macrophages, we investigated if LPL may play a role in microglial activation. To assess the function of LPL in the microglial inflammatory response, we utilized qPCR, Western blot, and immunofluorescence techniques. We show here that lipopolysaccharide (LPS) treatment induces LPL phosphorylation at serine 5, as well as increased Lcp1 mRNA expression. Furthermore, using a TAT‐fused peptidomimetic inhibitor of LPL phosphorylation significantly reduced LPS‐induced inflammatory gene (Il‐1b, Il‐6, Tnfa) expression. For this study, an acute 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP) mouse model was also used. Male (10‐week‐old) C57BL/6N mice were treated with four injections (one every two hours) of either saline or 15mg/kg of MPTP. Mice were then sacrificed two days after the last injection and striatum and hindbrain were isolated. Two days after MPTP treatment is when peak inflammation occurs in the brain. We found that Lcp1 mRNA expression was significantly increased in the striatum of MPTP‐treated mice compared to saline‐treated mice. These results suggest that LPL may play a role in the microglial inflammatory response, and that LPL inhibition may be a novel way to combat neuroinflammation and neurodegeneration. We are currently staining for phosphorylated LPL in the microglia of MPTP treated mice. Furthermore, we have obtained LPL KO mice to assess the in vivo function of LPL in mouse models of PD.Support or Funding InformationKent State University Biomedical Sciences