LAUSR

To date, the clinical diagnosis of Parkinson’s disease (PD) is based on the assessment of motor and nonmotor symptoms, risk factors, and the response to levodopa. However, many patients with PD suffer from a late and often uncertain diagnosis. In the future, successful treatment of the disease will depend essentially on our ability to facilitate early diagnosis and to detect even presymptomatic disease manifestations. The pathology of PD is associated with misfolded and aggregated α-synuclein protein. Thus, its detection in peripheral tissue or biofluids would represent a promising biomarker; however, inconsistent reports of α-synuclein levels have so far compromised this approach. In an attempt to address this challenge, Kluge and colleagues report that the detection of pathological α-synuclein conformers from neuronderived extracellular vesicles (EVs) in blood plasma samples allows for a reliable discrimination between patients and control subjects. Released from almost all types of cells, EVs are lipid bilayer structures carrying nucleic acids, lipids, and proteins, and they are able to pass the blood–brain barrier. They are important means of intercellular communication and potentially contribute to the pathogenesis of neurodegenerative diseases by spreading neuropathological proteins, for example, misfolded α-synuclein. Kluge and colleagues carried out a proof-of-concept study including 30 patients with idiopathic PD and 50 control subjects to detect misfolded α-synuclein in blood. They isolated EVs from plasma samples through gradual centrifugation and precipitation. From this pool, neuron-derived EVs were isolated through immunoprecipitation with an antibody against a neuronal marker. Soluble higher-molecular-weight forms of α-synuclein are thought to mediate neurotoxicity. Consequently, the authors used a structure-specific α-synuclein antibody to probe for these conformers in the soluble fraction of the neuron-derived EV lysates under nondenaturing conditions. Most importantly, they detected significantly increased α-synuclein signal intensities in the neuron-derived EVs from patients with PD compared with control subjects. Moreover, the pathological folding potential of the isolated α-synuclein species was subsequently confirmed in a seeding assay, exhibiting characteristic β-sheet-rich structures and a fibrillary appearance. This highly promising study provides the basis for a reliable and standardized blood test for PD. The experimental approach in its current form is technically challenging for routine diagnostics. However, once a simplified version has been established, this test may have an important impact on the (1) diagnostic accuracy, (2) determination and in-depth characterization of presymptomatic disease stage in a personalized fashion, and (3) application of interceptive medicine in the future to prevent irreparable brain damage.