Lewy-like aggregation of α-synuclein reduces protein phosphatase 2A activity in vitro and in vivo.
α-synuclein (α-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 α-Syn or triplication of wild type α-Syn, and in both PD and DLB the intraneuronal inclusions known as Lewy bodies contain aggregated α-Syn that is highly phosphorylated on serine 129. In neuronal cells and in the brains of α-Syn overexpressing transgenic mice, soluble α-Syn stimulates the activity of protein phosphatase 2A (PP2A), a major serine/threonine phosphatase. Serine 129 phosphorylation of α-Syn attenuates its stimulatory effects on PP2A and also accelerates α-Syn aggregation; however, it is unknown if aggregation of α-Syn into Lewy bodies impairs PP2A activity. To assess for this, we measured the impact of α-Syn aggregation on PP2A activity in vitro and in vivo. In cell-free assays, aggregated α-Syn had ∼50% less PP2A stimulatory effects than soluble recombinant α-Syn. Similarly in DLB and α-Syn triplication brains, which contain robust α-Syn aggregation with high levels of serine 129 phosphorylation, PP2A activity was also ∼50% attenuated. As α-Syn normally stimulates PP2A activity, our data suggest that overexpression of α-Syn or sequestration of α-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.
Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
J
J
Wu
H
H
Lou
T N M
TN
Alerte
E K
EK
Stachowski
J
J
Chen
A B
AB
Singleton
R L
RL
Hamilton
R G
RG
Perez
D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D020961:Lewy Body Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013379:Substrate Specificity / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*
C497604:SNCA protein, human; D051844:alpha-Synuclein; D054648:Protein Phosphatase 2