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

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Abstract

Fibrillar inclusions of intraneuronal α-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 α-synuclein oligomers appear harmful. Although it is incompletely known how the prefibrillar 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 α-synuclein propagation between neurons. Vesicular transfer of α-synuclein may thereby contribute to the hierarchical spreading of pathology seen in the PD brain. Although the regulation of α-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 α-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 α-synuclein in EVs could be developed as a future disease biomarker. Preferentially, toxic prefibrillar α-synuclein oligomers should then be targeted as a biomarker—as evidence suggests that they reflect the disease process more closely than total α-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 α-synuclein in different aggregational states.

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Acknowledgments

We thank Drs. Leonora Balaj and Xuan Zhang for valuable advice and guidance with the experimental part. Biospecimens were provided by the Harvard Biomarkers Study. The Harvard Biomarkers Study is co-directed by Drs. Clemens R. Scherzer, Bradley T. Hyman, and Adrian Ivinson and supported by the Harvard NeuroDiscovery Center (HNDC), the Parkinson’s Disease Biomarkers Program (PDBP) Grant U01 NS082157 of the NINDS (to C.R.S), a gift from Rick and Nancy Moskovitz (to A.J.I.) and the Massachusetts Alzheimer’s Disease Research Center (ADRC) P50 AG005134 Grant of the National Institute on Aging (to B.T.H.). CRS’ work is supported by NIH Grants U01 NS082157 and U01 NS082080, and U.S. Department of Defense Grant W81XWH-13-1-0115, as well as the M.E.M.O. Hoffman Foundation (C.R.S.).

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Authors and Affiliations

  1. Departments of Neurology and Radiology, Massachusetts General Hospital and Center for NeuroDiscovery, Harvard Medical School, Boston, MA, USA

    Camilla Lööv, Xandra O. Breakefield & Martin Ingelsson

  2. Departments of Neurology and Radiology, Massachusetts General Hospital and Alzheimer’s Disease Research Center, Harvard Medical School, Boston, MA, USA

    Bradley T. Hyman

  3. Neurogenomics Lab and Parkinson Personalized Medicine Program, Harvard Medical School, Brigham & Women’s Hospital, Cambridge, MA, 02139, USA

    Clemens R. Scherzer

  4. Department of Public Health, Molecular Geriatrics, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden

    Martin Ingelsson

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  1. Camilla Lööv
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  2. Clemens R. Scherzer
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  3. Bradley T. Hyman
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  4. Xandra O. Breakefield
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  5. Martin Ingelsson
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Correspondence to Martin Ingelsson.

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Lööv, C., Scherzer, C.R., Hyman, B.T. et al. α-Synuclein in Extracellular Vesicles: Functional Implications and Diagnostic Opportunities. Cell Mol Neurobiol 36, 437–448 (2016). https://doi.org/10.1007/s10571-015-0317-0

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  • DOI: https://doi.org/10.1007/s10571-015-0317-0

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