α-Synuclein is phosphorylated in synucleinopathy lesions

Abstract

The deposition of the abundant presynaptic brain protein alpha-synuclein as fibrillary aggregates in neurons or glial cells is a hallmark lesion in a subset of neurodegenerative disorders. These disorders include Parkinson's disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy, collectively referred to as synucleinopathies. Importantly, the identification of missense mutations in the alpha-synuclein gene in some pedigrees of familial PD has strongly implicated alpha-synuclein in the pathogenesis of PD and other synucleinopathies. However, specific post-translational modifications that underlie the aggregation of alpha-synuclein in affected brains have not, as yet, been identified. Here, we show by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of alpha-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions. Furthermore, phosphorylation of alpha-synuclein at Ser 129 promoted fibril formation in vitro. These results highlight the importance of phosphorylation of filamentous proteins in the pathogenesis of neurodegenerative disorders.

Detection of alpha‐synuclein conformational variants from gastro‐intestinal biopsy tissue as a potential biomarker for Parkinson's disease

“…We found no difference in specificity whether we used O/P‐aSyn‐Ab. Although phosphorylation is generally considered a marker of choice to delineate pathological aggregates from normal, native aSyn accumulation 35, using the P‐aSyn‐Ab, Bottner et al . 17 and Visanji et al .…”

Are amyloid diseases caused by protein aggregates that mimic bacterial pore-forming toxins?

“…Several studies of a-synuclein aggregates extracted from brains affected by rare neurodegenerative diseases related to PD, provide tantalizing evidence that pore-like structures do exist in vivo. Several studies of a-synuclein fibrils from diffuse Lewy body disease (DLBD) reveal pore-like structures that co-purify with a-synuclein fibrils (Spillantini et al 1998a ;Fujiwara et al 2002). The resemblance of these structures to the amyloid pores produced from a-synuclein in vitro (Lashuel et al 2002a) is striking.…”

Dysregulation of protein phosphatase 2A in parkinson disease and dementia with lewy bodies

“…In relation to α ‐synucleinopathies in particular, PP2A catalyzes the dephosphorylation of phospho‐Ser 129 α ‐synuclein, and the methylation state of the PP2A C subunit regulates this activity 13. Accordingly, the finding of decreased PP2A methylation in this study provides a molecular mechanism for the reduced PP2A activity reported in α ‐synucleinopathies 16 and is likely a significant contributor to the hyperphosphorylation of aggregated α ‐synuclein in these disorders 10, 29…”

“…Pathologic α ‐synuclein accumulation itself may be an inhibitor of PP2A activity resulting in a vicious cycle exacerbating the hyperphosphorylation and aggregation of pathogenic proteins including α ‐synuclein and tau in Lewy body disease 10, 45. Overexpression of α ‐synuclein, particularly its A53T mutant which causes dominantly inherited PD and dementia, increases intracellular levels of reactive oxygen species in SH‐SY5Y neuroblastoma cells ,46 contributing to oxidative stress‐mediated dysregulation of PP2A 42, 44.…”

“…α ‐Synuclein is extensively phosphorylated at Ser 129 in PD and DLB brains 10, 11, 12. Additionally, hyperphosphorylated and misfolded α ‐synuclein accumulates in neurons of transgenic mice that express human α ‐synuclein,11, 13 and hyperphosphorylation exacerbates α ‐synuclein toxicity in Drosophila 14.…”