Significance and confounders of peripheral DJ-1 and alpha-synuclein in Parkinson's disease

Abstract

DJ-1 and α-synuclein are leading biomarkers for Parkinson disease diagnosis and/or monitoring disease progression. A few recent investigations have determined DJ-1 and α-synuclein levels in plasma or serum, a more convenient sample source than cerebrospinal fluid; but the results were variable or even contradictory. Besides limitations in detection technology and limited number of cases in some studies, inadequate control of several important confounders likely has contributed to these inconsistent results. In this study, the relative contribution of each blood component to blood DJ-1 and α-synuclein was evaluated, followed by quantification of plasma levels of both markers in a larger cohort of patients/subjects (~300 cases) whose cerebrospinal fluid DJ-1 and α-synuclein levels have been determined recently. The results demonstrated that the DJ-1 and α-synuclein in blood resided predominantly in red blood cells (>95%), followed by platelets (1-4%), white blood cells and plasma (≤1%), indicating that variations in hemolysis and/or platelet contamination could have a significant effect on plasma/serum DJ-1 and α-synuclein levels. Nonetheless, after adjusting for the age, although there was a trend of decrease in DJ-1 and α-synuclein in patients with Parkinson or Alzheimer disease compared with healthy controls, no statistical difference was observed in this cohort between any groups, even when the extent of hemolysis and platelet contamination were controlled for. Additionally, no correlation between DJ-1 or α-synuclein and Parkinson disease severity was identified. In conclusion, unlike in cerebrospinal fluid, total DJ-1 or α-synuclein in plasma alone is not useful as biomarkers for Parkinson disease diagnosis or progression/severity.

Blood and cerebrospinal fluid markers in Parkinson's disease: current biomarker findings

“…In plasma, total 26 and oligomeric 13 α-synuclein has been increased in PD, but this has not been replicated in other studies. 15,27,28 It has been proposed that variations in sample collection and possibly hemolysis might lead to variability in measures, as the vast majority of α-synuclein is present in red blood cells.…”

“…As with α-synuclein, in blood the overwhelming majority of the protein is contained within blood cells and platelets, making sample preparation demanding, and with variable hemolysis or residual platelets in samples leading to a potential source of noise. 27 This may account for contradictory results published in plasma. 58,59 CSF measures may therefore turn out to be more robust.…”

“…60 Moreover, although levels may be associated with the diagnosis of PD, DJ-1 does not seem on the basis of current studies to be a marker of disease severity. 25,27 As with α-synuclein, however, DJ-1 exists in multiple forms. It will likely be important to define which will be most helpful as biomarkers.…”

The Hsp70 Chaperone System in Parkinson’s Disease

“…DJ-1, which is the only chaperone to be included in this study, is a mitochondrial chaperone which has been one of the most studied proteins for its potential use as a PD biomarker. However, results published thus far from measurements of DJ-1 in CSF (Hong et al, 2010) and serum from PD patients (Hong et al, 2010;Shi et al, 2010;Waragai et al, 2007) are somewhat controversial or inconsistent, which could probably be explained by the high DJ-1 protein level present in blood cells (Shi et al, 2010). Currently, it is well established that certain proteins, including members of the Hsp70 family such as Hsp701A and 1B, display perturbed expression levels in the SN of PD brains (Hauser et al, 2005); however, changes in tissue expression levels are in principle not useful for an application as biomarkers.…”

Accessing to the minor proteome of red blood cells through the influence of the nanoparticle surface properties on the corona composition

“…This access to the minor RBC proteome could also provide precious information for non-hematological disorders. For instance, the specific identification by NP treatment of alpha-synuclein and DJ-1, 45 two major proteins associated to Parkinson's disease, 46,47 may open the way to new proteomics analysis of RBCs in this disease. 48,49 Finally, one great advantage of our approach, in comparison with immuno-depletion 36 or ProteoMiner, 37 concerns its efficiency from low volume of sample (200 µL of RBC containing 1 mg of protein).…”