Abstract
Alpha-synuclein protein is strongly implicated in the pathogenesis Parkinson's disease. Increased expression of α-synuclein due to genetic multiplication or point mutations leads to early onset disease. While α-synuclein is known to modulate membrane vesicle dynamics, it is not clear if this activity is involved in the pathogenic process or if measurable physiological effects of α-synuclein over-expression or mutation exist in vivo. Macrophages and microglia isolated from BAC α-synuclein transgenic mice, which overexpress α-synuclein under regulation of its own promoter, express α-synuclein and exhibit impaired cytokine release and phagocytosis. These processes were affected in vivo as well, both in peritoneal macrophages and microglia in the CNS. Extending these findings to humans, we found similar results with monocytes and fibroblasts isolated from idiopathic or familial Parkinson's disease patients compared to age-matched controls. In summary, this paper provides 1) a new animal model to measure α-synuclein dysfunction; 2) a cellular system to measure synchronized mobilization of α-synuclein and its functional interactions; 3) observations regarding a potential role for innate immune cell function in the development and progression of Parkinson's disease and other human synucleinopathies; 4) putative peripheral biomarkers to study and track these processes in human subjects. While altered neuronal function is a primary issue in PD, the widespread consequence of abnormal α-synuclein expression in other cell types, including immune cells, could play an important role in the neurodegenerative progression of PD and other synucleinopathies. Moreover, increased α-synuclein and altered phagocytosis may provide a useful biomarker for human PD.
Highlights
The evidence implicating alpha-synuclein (a-syn) in the pathogenesis of Parkinson’s Disease (PD) is overwhelming
We have recently developed a novel transgenic genomic mouse model in which wild type or the E46K mutant form of human asyn was expressed from a human bacterial artificial chromosome (BAC)
We demonstrate this effect in microglia and macrophages isolated from novel a-syn BAC transgenic mice that exhibit modest a-syn over expression via endogenous human a-syn gene promoter elements
Summary
The evidence implicating alpha-synuclein (a-syn) in the pathogenesis of Parkinson’s Disease (PD) is overwhelming. Targeted siRNA knockdown of human asyn restored phagocytosis in a-syn TG macrophages while having minimal activity on non-TG cells (Figure 5B) These data reinforce the notion that elevated a-syn levels, rather than aberrant developmental changes are responsible for the observed phagocytic defects in the BAC transgenic animals. To assess the effects of different PD-associated a-syn mutants on vesicle function, A53T, E46K and A30P a-syn constructs were transfected into H4 cells and all three mutations were found to significantly block phagocytosis as well as wild type a-syn when compared to vector transfected cells (Figure 5E) and this effect was dose-responsive to the level of a-syn expressed, with A53T and E46K having the greatest effect (data not shown). Defective phagocytosis significantly correlated with elevated intracellular a-syn levels (Figure 9E)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
