Posttranslational modifications of blood-derived alpha-synuclein as biochemical markers for Parkinson’s disease

Abstract

Parkinson’s disease (PD) is a progressive neurodegenerative disorder known for the typical motor features associated. Pathologically, it is characterized by the intracellular accumulation of alpha-synuclein (aSyn) in Lewy bodies and Lewy neurites. Currently, there are no established biochemical markers for diagnosing or for following disease progression, a major limitation for the clinical practice. Posttranslational modifications (PTMs) in aSyn have been identified and implicated on its pathobiology. Since aSyn is abundant in blood erythrocytes, we aimed to evaluate whether PTMs of aSyn in the blood might hold value as a biomarker for PD. We examined 58 patients with PD and 30 healthy age-matched individuals. We found that the levels of Y125 phosphorylated, Y39 nitrated, and glycated aSyn were increased in PD, while those of SUMO were reduced. A combinatory analysis of the levels of these PTMs resulted in an increased sensitivity, with an area under curve (AUC) of 0.843 for PD versus healthy controls, and correlated with disease severity and duration. We conclude that the levels of these selected PTMs hold strong potential as biochemical markers for PD. Ultimately, our findings might facilitate the monitoring of disease progression in clinical trials, opening the possibility for developing more effective therapies against PD.

GlialHMOX1expression promotes central and peripheral α‐synuclein dysregulation and pathogenicity in parkinsonian mice

“…Moreover, 19 month‐old TG mice displayed significantly increased levels of α‐synuclein protein in RBCs, both in its monomeric (two‐fold increase, p = .002) and oligomeric (1.5‐fold increase, p = .004) forms, compared to WT preparations (Figure c,d). The latter observations correspond with, and may hint at a mechanism responsible for, increases in α‐synuclein protein concentrations reported in RBCs of PD patients (Matsumoto et al, ; Nakai et al, ; Vicente Miranda et al, ). In contrast to miR‐153, the decline in serum miR‐223 with age did not differ significantly between the TG and WT animals ( p = .2) (Figure b), suggesting that the relative contribution of miR‐223 to peripheral α‐synuclein dysregulation in this model is minimal.…”

“…miR‐153 levels were significantly lower in GFAP.HMOX1 serum than WT serum at each time point surveyed, suggesting that miR‐153, more so than miR‐223, may be responsible for upregulation of peripheral α‐synuclein expression under pathological (parkinsonian) conditions. In support of this formulation, both monomeric and oligomeric forms of α‐synuclein protein were significantly increased in RBCs of 19‐month old GFAP.HMOX1 mice compared to age‐matched WT mice, and as previously documented in human PD blood (Matsumoto et al, ; Nakai et al, ; Vicente Miranda et al, ). miR‐153 has been previously implicated in the neuroepithelial cell response to ethanol toxicity, likely accounting for the lower levels of miR‐153 and higher blood cell α‐synuclein mRNA concentrations observed in alcoholic subjects (Walker & Grant, ).…”

Salivary microR‐153 and microR‐223 Levels as Potential Diagnostic Biomarkers of Idiopathic Parkinson's Disease

“…Expression levels of miR‐153, miR‐223 and the gene encoding α‐synuclein, SNCA are highest in midbrain, although they have also been detected in extracellular compartments, including blood, CSF, and saliva, where their levels appear to fluctuate in response to disease state. Several groups, including our own, have linked miR‐153 and, to a lesser extent, miR‐223 to PD pathology .…”

Systemic Activation of Nrf2 Pathway in Parkinson's Disease

“…Despite the limitations as the result of a relatively small sample size and the substantial homogeneous features (eg, early stages, mild–moderate presentation, strict selection criteria) of the population, Our findings suggest a potential interplay between the Nrf2 pathway and disease duration, indicating a compensatory attempt during the progression of the neurodegenerative process. Instead, the lowering of α‐syn oligomer levels found in patients with longer disease duration could theoretically reflect the fluctuations as a result of neuropathological modifications of PD during the disease course …”