Phosphorylated α-synuclein in Parkinson’s disease: correlation depends on disease severity

Abstract

Introductionα-Synuclein (α-syn) is a key protein in Parkinson’s disease (PD), and one of its phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of LRRK2 mutation carriers).ResultsConsistent with our previous observation that CSF pS129 positively correlated with Unified Parkinson’s Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort increased over approximately two years of disease progression (mean change 5.60 pg/ml, p = 0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores at the baseline (R = −0.244, p = 0.017), but not final point, suggesting that this association may depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the idea that the relationship between CSF pS129 and disease severity over a wider range of PD stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with worse clinical condition at early stages, but better condition at later stages.ConclusionThe observation of a negative-to-positive transition of correlation of pS129 to disease severity as PD progresses could have profound impact on how pS129 is used as a biomarker clinically as well as in modeling PD experimentally.

Alpha-, Beta-, and Gamma-synuclein Quantification in Cerebrospinal Fluid by Multiple Reaction Monitoring Reveals Increased Concentrations in Alzheimer′s and Creutzfeldt-Jakob Disease but No Alteration in Synucleinopathies

“…For instance, several studies observed increased Ser 129 P-␣Syn concentrations in CSF of PD patients (48,49). However, the measurement of the C-terminal peptide of ␣Syn (␣Syn103-140) was not possible in the present MRM as discussed above.…”

“…There was no specific pattern of the peptides for synucleinopathies and atypical parkinsonian syndromes. However, the determination of specific PTMs might be more sensitive as has been shown for Ser 129 P-␣Syn (48,49) and should be the focus of future mass spectrometric improvements for the characterizations of ␣Syn in CSF. This is the first study presenting quantitative data on ␤Syn and ␥Syn in CSF.…”

A Longitudinal Study of Total and Phosphorylated α-Synuclein with Other Biomarkers in Cerebrospinal Fluid of Alzheimer’s Disease and Mild Cognitive Impairment

“…Importantly, most α-syn present in LBs is highly phosphorylated, especially at serine 129 (pS129) [15, 20–22], which is thought to alter aggregation and toxicity of α-syn[23, 24]. Notably, the CSF pS129 was significantly higher in PD patients than in healthy controls, and correlated with PD severity[16, 25], suggesting it may serve as a marker of PD pathology independently of total α-syn, which tends to be lower in the CSF of PD patients[18, 26–29]. However, the roles of these biomarkers in AD have not yet been completely probed, particularly considering pS129 in large, longitudinal cohorts.…”

Modification of α-Synuclein by Phosphorylation: A Pivotal Event in the Cellular Pathogenesis of Parkinson’s Disease

“…In addition, pSyn inclusions were also detected in the PNS which might also serve as a useful diagnostic test for PD and related synucleinopathies. Work from two independent groups on skin biopsies showed that the majority of PD patients had accumulation of pSyn in small and large nerve fibers, while no signal was detected in healthy controls and in MSA or essential tremor control subjects [133,134]. This cutaneous pathology was correlated with the progression of disease symptoms suggesting the use of this peripheral marker as a biomarker for the disease [135].…”