Osteopontin (OPN), a glycosylated phosphoprotein, is down regulated in remaining dopaminergic neurones in Parkinson’s disease. It has protective properties including anti-inflammatory and anti-apoptotic effects. Therefore, it was hypothesised that OPN treatment protects dopaminergic neurons from toxin induced cell death, and its endogenous expression in cells confers intrinsic protection. Consequently, OPN was investigated for neuroprotective effects in toxin models of dopaminergic cell death using SH-SY5Y and N1E-115 cell lines with different OPN expression phenotypes, primary E14 ventral meseneephalic (VM) culture and rats. -- Cell lines expressed receptors linked to the pro-survival effects of OPN (Igαv, Igβ3, Igβ1 and CD44). However, endogenous OPN expression did not affect vulnerability of cell lines to the toxins MPP+ or H2O2 and exogenous pre-treatment with OPN did not protect them from toxin-induced cell death. By contrast, pre-treatment of VM cultures with OPN protected them against MPP+-induced dopaminergic cell loss. Importantly, a 15-mer peptide fragment of OPN containing the ROD integrin binding site retained protective properties of OPN. Further, treatment with the integrin receptor antagonists, RGDS and GRGDSPK, prevented OPN’s protective effect, suggesting a role for integrins in the protective effect. OPN induced an increase in the number of microglia in VM cultures but the role of glial cells in OPN’s protective effect is not fully clear. In the LPS lesioned rats, there was an up-regulation of the expression of Igαv, Igβ3, Igβ1 and CD44 receptors and prior intra-nigral OPN injection protected dopaminergic cells of the substantia nigra against LPS toxicity. Immunohistochemical investigation revealed that OPN significantly decreased the inflammatory microgliosis produced by LPS.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:634178 |
| Date | January 2012 |
| Creators | Ailane, Sara |
| Publisher | King's College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | https://kclpure.kcl.ac.uk/portal/en/theses/the-neuroprotective-role-of-osteopontin-in-invitro-and-invivo-models-of-parkinsons-disease(266aa361-e9b6-413d-9df8-c87b00445b49).html |
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