Abstract
Intensive research efforts in the field of Parkinson’s disease (PD) are focusing on identifying reliable biomarkers which possibly help physicians in predicting disease onset, diagnosis, and progression as well as evaluating the response to disease-modifying treatments. Given that abnormal alpha-synuclein (α-syn) accumulation is a primary component of PD pathology, this protein has attracted considerable interest as a potential biomarker for PD. Alpha-synuclein can be detected in several body fluids, including plasma, where it can be found as free form or in association with exosomes, small membranous vesicles secreted by virtually all cell types. Together with α-syn accumulation, lysosomal dysfunctions seem to play a central role in the pathogenesis of PD, given the crucial role of lysosomes in the α-syn degradation. In particular, heterozygous mutations in the GBA1 gene encoding lysosomal enzyme glucocerebrosidase (GCase) are currently considered as the most important risk factor for PD. Different studies have found that GCase deficiency leads to accumulation of α-syn; whereas at the same time, increased α-syn may inhibit GCase function, thus inducing a bidirectional pathogenic loop. In this study, we investigated whether changes in plasma total and exosome-associated α-syn could correlate with disease status and clinical parameters in PD and their relationship with GCase activity. We studied 39 PD patients (mean age: 65.2 ± 8.9; men: 25), without GBA1 mutations, and 33 age-matched controls (mean age: 61.9 ± 6.2; men: 15). Our results showed that exosomes from PD patients contain a greater amount of α-syn compared to healthy subjects (25.2 vs. 12.3 pg/mL, p < 0.001) whereas no differences were found in plasma total α-syn levels (15.7 vs. 14.8 ng/mL, p = 0.53). Moreover, we highlighted a significant increase of plasma exosomal α-syn/total α-syn ratio in PD patients (1.69 vs. 0.89, p < 0.001), which negatively correlates with disease severity (p = 0.014). Intriguingly, a significant inverse correlation between GCase activity and this ratio in PD subjects was found (p = 0.006). Additional and large-scale studies comparing GCase activity and pathological protein levels will be clearly needed to corroborate these data and determine whether the association between key players in the lysosomal system and α-syn can be used as diagnostic or prognostic biomarkers for PD.
Highlights
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN)
Exosomes isolated from plasma of healthy subjects and patients were evaluated by Transmission Electron Microscopy (TEM), Western blot and Nanosight to confirm the reliability of isolation protocol and the purity of exosome preparations
In order to evaluate whether the presence of lipoproteins in our samples could cause false positive hits in the analyses, we measured the concentration of high-density lipoprotein (HDL) and low-density lipoprotein (LDL) in plasma, exosome-enriched fraction and exosome-poor plasma from independent samples
Summary
Parkinson’s disease (PD) is a common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). In PD there is a large time-gap between the beginning of the neurodegenerative processes and the onset of clinical manifestations, since motor symptoms are developing when there is already approximately 60%–80% of striatal dopaminergic loss (Cooper and Chahine, 2016). The identification of reliable PD-specific biomarkers able to recognize individuals ‘‘at risk’’ before motor symptoms appear, improve PD diagnosis and monitor disease progression is a critical unmet need in the field. The development of biochemical markers is most logically based on the understanding of processes involved in disease pathogenesis and progression. Α-syn can be detected in several body fluids (Malek et al, 2014). Conflicting results obtained in studies on α-syn species in CSF further stimulated biomarker discovery in these biological fluids (Malek et al, 2014)
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