α‐Synuclein Pathology in <scp><i>PRKN</i></scp>‐Linked Parkinson's Disease: New Insights from a Blood‐Based Seed Amplification Assay
Annika Kluge, Max Borsche, Linn Streubel‐Gallasch, Tuğçe Gül, Susen Schaake, Alexander Balck, Jannik Prasuhn, Philip Campbell, Huw R. Morris, Anthony H.V. Schapira, Katja Lohmann, Norbert Brüggemann, Aleksandar Raković, Philip Seibler, A. Nazlı Başak, Daniela Berg, Christine Klein
Abstract
Pathogenic variants in PRKN cause early-onset Parkinson's disease (PD), while the role of alpha-synuclein in PRKN-PD remains uncertain. One study performed a blood-based alpha-synuclein seed amplification assay (SAA) in PRKN-PD, not detecting seed amplification in 17 PRKN-PD patients. By applying a methodologically different SAA focusing on neuron-derived extracellular vesicles, we demonstrated alpha-synuclein seed amplification in 8 of 13 PRKN-PD patients, challenging the view of PRKN-PD as a non-synucleinopathy. Moreover, we performed blinded replication of the neuron-derived extracellular vesicles-dependent SAA in idiopathic PD patients and healthy controls. In conclusion, blood-based neuron-derived extracellular vesicles-dependent SAA represents a promising biomarker to elucidate the underpinnings of (monogenic) PD. ANN NEUROL 2024;95:1173-1177.