α-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities

Fibrillar inclusions of intraneuronal alpha-synuclein can be detected in certain brain areas from patients with Parkinson's disease (PD) and other disorders with Lewy body pathology. These insoluble protein aggregates do not themselves appear to have a prominent neurotoxic effect, whereas various alpha-synuclein oligomers appear harmful. Although it is incompletely known how the pre-fibrillar species may be pathogenic, they have been detected both within and on the outside of exosomes and other extracellular vesicles (EVs), suggesting that such structures may mediate toxic alpha-synuclein propagation between neurons. Vesicular transfer of alpha-synuclein may thereby contribute to the hierarchical spreading of pathology seen in the PD brain. Although the regulation of alpha-synuclein release via EVs is not understood, data suggest that it may involve other PD-related molecules, such as LRRK2 and ATP13A2. Moreover, new evidence indicates that CNS-derived EVs in plasma have the potential to serve as biomarkers for diagnostic purposes. In a recent study, levels of alpha-synuclein were found to be increased in L1CAM-positive vesicles isolated from plasma of PD patients compared to healthy controls, and follow-up studies will reveal whether alpha-synuclein in EVs could be developed as a future disease biomarker. Preferentially, toxic prefibrillar alpha-synuclein oligomers should then be targeted as a biomarker-as evidence suggests that they reflect the disease process more closely than total alpha-synuclein content. In such studies, it will be essential to adopt stringent EV isolation protocols in order to avoid contamination from the abundant pool of free plasma alpha-synuclein in different aggregational states.