Aggregation-resistant alpha-synuclein tetramers are reduced in the blood of Parkinson’s patients
Laura de Boni, Amber Wallis, Aurelia Hays Watson, Alejandro Ruiz‐Riquelme, Louise‐Ann Leyland, Thomas Bourinaris, Naomi Hannaway, Ullrich Wüllner, Oliver Peters, Josef Priller, Björn Falkenburger, Jens Wiltfang, Mathias Bähr, Inga Zerr, Katharina Bürger, Robert Perneczky, Stefan Teipel, Matthias Löhle, Wiebke Hermann, Björn H. Schott, Kathrin Brockmann, Annika Spottke, Katrin Haustein, Péter Breuer, Henry Houlden, Rimona S. Weil, Tim Bartels
Abstract
Synucleinopathies such as Parkinson's disease (PD) are defined by the accumulation and aggregation of the α-synuclein protein in neurons, glia and other tissues. We have previously shown that destabilization of α-synuclein tetramers is associated with familial PD due to SNCA mutations and demonstrated brain-region specific alterations of α-synuclein multimers in sporadic PD patients following the classical Braak spreading theory. In this study, we assessed relative levels of disordered and higher-ordered multimeric forms of cytosolic α-synuclein in blood from familial PD with G51D mutations and sporadic PD patients. We used an adapted in vitro-cross-linking protocol for human EDTA-whole blood. The relative levels of higher-ordered α-synuclein tetramers were diminished in blood from familial PD and sporadic PD patients compared to controls. Interestingly, the relative amount of α-synuclein tetramers was already decreased in asymptomatic G51D carriers, supporting the hypothesis that α-synuclein multimer destabilization precedes the development of clinical PD. Our data, therefore suggest that measuring α-synuclein tetramers in blood may have potential as a facile biomarker assay for early detection and quantitative tracking of PD progression.