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Novel Regulators of Neuroinflammation and Neuroprotection

Budge, Kevin Mark
http://rave.ohiolink.edu/etdc/view?acc_num=kent1605867905185808

Abstract Details

2020, PHD, Kent State University, College of Arts and Sciences / School of Biomedical Sciences.
Parkinson’s disease (PD) is a common neurodegenerative disease predominantly affecting the elderly. Classic hallmarks of PD pathology include the drastic loss of dopaminergic neurons in the substantia nigra and the formation of α-synuclein-containing Lewy bodies in the remaining neurons. Currently, no therapies have proven effective in slowing or stopping the progression of the disease. Therefore, the development of a novel disease modifying therapy is of great importance. Neuroinflammation plays an integral role in the pathogenesis of PD and strategies to combat neuroinflammation represent a promising treatment avenue. Glycoprotein nonmetastatic melanoma protein B (GPNMB) may represent a possible therapy for PD. GPNMB levels are increased in human PD brain samples suggesting it may play a role in the disease. Additionally, GPNMB has been shown to be neuroprotective in an ALS mouse model, a cerebral ischemia and reperfusion mouse model, and is anti-inflammatory in astrocytes. Another factor that may play a role in neurodegeneration and neuroinflammation is the actin bundling protein L-plastin (LPL). There aren’t many studies examining LPL in neurodegeneration or neuroinflammation, but LPL KO mice have a less severe phenotype and reduced inflammation compared to wild-type mice in a mouse model of autoimmune encephalomyelitis. LPL is also involved with NLRP3 inflammasome activation and NADPH oxidase function, so inhibiting LPL may have an anti-inflammatory effect. In this dissertation, we showed that transgenic overexpression of GPNMB protected against MPTP-induced neurodegeneration. Furthermore, we showed that GPNMB overexpression prevented against MPTP-induced gliosis and microglial morphological changes. Additionally, in primary mouse microglia, we showed that recombinant GPNMB reduced LPS-induced increases in inflammatory gene expression and increased anti-inflammatory gene expression. This suggests that GPNMB may be stimulating microglia towards an M2 anti-inflammatory phenotype. In another study we evaluated the role of LPL in inflammation using MMC microglial cells in vitro and in LPL KO mice in vivo. In MMC cells, we show that lipopolysaccharide (LPS) induced an increase in LPL phosphorylation, but pre-treatment with an LPL inhibitory peptide (LPP) reduced the LPS-induced phosphorylation. Furthermore, we showed that the LPP significantly reduced the LPS-induced increase in inflammatory gene expression assessed by qPCR. Thus, we hypothesized LPL ablation would have an anti-inflammatory effect in vivo. We treated wild-type and LPL KO mice with LPS intraperitoneally and sacrificed the mice 24 hours later. We measured inflammatory markers in the striatum by qPCR and performed immunohistochemistry for Iba1 in the substantia nigra. We found that LPS induced inflammation in both wild-type and LPL KO mice, but found no statistical difference between wild-type and LPL KO mice. In summary, our results suggest a neuroprotective and anti-inflammatory role for GPNMB. For LPL, further studies are needed to determine its role in inflammation.
Fayez Safadi, Ph.D. (Advisor)
Derek Damron, Ph.D. (Committee Member)
Edgar Kooijman, Ph.D. (Committee Member)
Eric Mintz, Ph.D. (Committee Member)
Jason Richardson, Ph.D. (Committee Member)
235 p.
Biology; Biomedical Research
Parkinsons Disease; Neuroinflammation; Neurodegeneration; Neuroprotection

Recommended Citations

Citations

  • Budge, K. M. (2020). Novel Regulators of Neuroinflammation and Neuroprotection [Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1605867905185808

    APA Style (7th edition)

  • Budge, Kevin. Novel Regulators of Neuroinflammation and Neuroprotection. 2020. Kent State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=kent1605867905185808.

    MLA Style (8th edition)

  • Budge, Kevin. "Novel Regulators of Neuroinflammation and Neuroprotection." Doctoral dissertation, Kent State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=kent1605867905185808

    Chicago Manual of Style (17th edition)

kent1605867905185808
221
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This open access ETD is published by Kent State University and OhioLINK.