Parkinson’s disease (PD) is a neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. PINK1 is a well-known autosomal recessive familial PD gene, expressed in both neurons and glia. In this study, I analyzed the roles of PINK1 in brain inflammation using slice cultures prepared from PINK1 knockout (KO) and wild type (WT) mice since slicing mimics injury. For up to 24 h after slicing, mRNA expression levels of pro-inflammatory cytokines (TNF-a, IL-1b, and IL-6) measured at 6 to 24h were higher in KO slices. Expression of inducible nitric oxide synthase (iNOS) was not detected in either KO or WT slices. Furthermore, nitrite production was continuously increased for up to 72 h in both WT and KO slices. There was no difference in the production levels, which suggests that nitrite production was from nitrogen containing metabolites rather than from the action of iNOS. Enhanced inflammatory responses in PINK1 deficiency was independently of cell death. In serial investigation of inflammatory signaling pathways, KO slices comparing to WT slices showed lower activation levels of STAT3 and Akt, and enhanced IkB degradation. STAT3 has been known to inhibit IkB degradation, and I found that an Akt inhibitor, LY294002, increased the expression of pro-inflammatory cytokines. These results suggest that PINK1 deficiency enhances the expression of pro-inflammatory cytokines through reduced STAT3 and Akt activation, enhanced IkB degradation in response to brain injury.
PINK1, Parkinson's disease, inflammation
Networked Digital Library of Theses and Dissertations