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.
Highlights
Parkinson’s disease (PD) is a common age-related neurodegenerative disease, with a complicated etiology featuring both genetic and environmental components [1,2]
Longitudinal alteration of phosphorylated α-syn in cerebrospinal fluid (CSF) We tested the change in phosphorylation at serine 129 (pS129) and the pS129/α-syn ratio over the two-year DATATOP follow-up period
We examined separately the subset of patients who reached endpoint, and found that the differences between final and baseline scores for pS129 and pS129/α-syn ratio were somewhat larger, indicating that the changes are more pronounced in the subset of subjects that progressed to requiring levodopa therapy (Table 2; Figure 1)
Summary
Parkinson’s disease (PD) is a common age-related neurodegenerative disease, with a complicated etiology featuring both genetic and environmental components [1,2]. Considerable controversy exists over the effects of pS129 on neurodegeneration in PD, with contradictory findings in transgenic fly [10] and mammalian models studying effects of phosphorylation on α-syn toxicity [11,15] and neurodegeneration [16]. These contrasts suggest that the effects of pS129 may be highly modeldependent, making assessment of the natural course of pS129 in human disease imperative for more accurate
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