| Parkinson's disease (PD) is an age-related slowly progressive neurodegenerative disorder with preferential loss of nigrostriatal dopamine neurons. The pathological hallmark of PD is the presence of intracytoplasmic proteinaceous synuclein positive inclusions, so-called Lewy bodies, in the remaining dopaminergic neurons. It is well documented that over-expression of wild-type (WT) alpha-synuclein (SYN) or mutant forms, A30P and A53T, play an important role in the pathogenesis of PD. In addition, a growing body of evidence suggests an inflammatory process in the substantia nigra (SN) and striatum (STR), characterized by activation of resident microglial cells in PD patients. Based on this information, we hypothesize that overexpression of WT and mutant SYN will induce microglial-mediated inflammation. Furthermore, we posit that activation of microglia will exacerbate nigrostriatal pathology. To test this hypothesis, we used two transgenic mouse models as well as primary microglial-enriched cell cultures. The first model utilizes human WT SYN overexpression exclusively in tyrosine hydroxylase (TH) containing cells (SYNWT+/+) while the second model employs a similar strategy for overexpression of doubly-mutated human SYN (A30P and A53T, SYNDM+/+). Utilizing these transgenic models, we determined microglial activation at various ages compared with non-transgenic animals (NTG) and characterized upregulated inflammatory molecules. Furthermore, to examine the direct effect of SYN on microglial activation, we utilized primary microglia-enriched cultures from non-transgenic mice treated with WT and DM SYN. Finally, primary microglia-enriched cell cultures from CD36-deficient mice (CD36-/-) were used to determine the necessity of this scavenger receptor for SYN phagocytosis. Together, the results of these studies demonstrated that an early microglia-mediated inflammation occurred in both SYNWT +/+ and SYNDM+/+ transgenic mice, and the degree of inflammation in SYNDM+/+ was much greater than in SYNWT+/+. Furthermore, the early and transient microglial activation in SYNDM+/+ mice was associated with delayed degeneration of striatal nerve terminals within 12 months. In vitro studies showed that both WT and DM SYN were able to activate microglia directly and induce a cascade of inflammatory events, which processes are partially mediated by CD36. To conclude, these studies reveal the pathological effect of SYN overexpression or mutation in triggering microglial activaton as well as the neurotoxic role of microglial activation in dopaminergic neuron dysfunction in the SYN-related transgenic models of Parkinson's disease. |
