LEWY-LIKE AGGREGATION OF α-SYNUCLEIN REDUCES PROTEIN PHOSPHATASE 2A ACTIVITY IN VITRO AND IN VIVO

alpha-synuclein (alpha-Syn) is a chaperone-like protein that is highly implicated in Parkinson's disease (PD) as well as in dementia with Lewy bodies (DLB). Rare forms of PD occur in individuals with mutations of alpha-Syn or triplication of wild type alpha-Syn, and in both PD and DLB the intraneuronal inclusions known as Lewy bodies contain aggregated alpha-Syn that is highly phosphorylated on serine 129. In neuronal cells and in the brains of alpha-Syn overexpressing transgenic mice, soluble alpha-Syn stimulates the activity of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase. Serine 129 phosphorylation of alpha-Syn attenuates its stimulatory effects on PP2A and also accelerates alpha-Syn aggregation; however, it is unknown if aggregation of alpha-Syn into Lewy bodies impairs PP2A activity. To assess for this, we measured the impact of alpha-Syn aggregation on PP2A activity in vitro and in vivo. In cell-free assays, aggregated alpha-Syn had similar to 50% less PP2A stimulatory effects than soluble recombinant alpha-Syn. Similarly in DLB and alpha-Syn triplication brains, which contain robust alpha-Syn aggregation with high levels of serine 129 phosphorylation, PP2A activity was also similar to 50% attenuated. As alpha-Syn normally stimulates PP2A activity, our data suggest that overexpression of alpha-Syn or sequestration of alpha-Syn into Lewy bodies has the potential to alter the phosphorylation state of key PP2A substrates; raising the possibility that all forms of synucleinopathy will benefit from treatments aimed at optimizing PP2A activity. (C) 2012 IBRO. Published by Elsevier Ltd. All rights reserved.