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alpha-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients
Karolinska Inst, Dept Clin Neurosci, Neuro Svenningsson, S-17176 Stockholm, Sweden.
Karolinska Inst, Dept Clin Neurosci, Neuro Svenningsson, S-17176 Stockholm, Sweden.
Karolinska Inst, Dept Clin Neurosci, Neuro Svenningsson, S-17176 Stockholm, Sweden.
Karolinska Inst, Dept Clin Neurosci, Neuro Svenningsson, S-17176 Stockholm, Sweden.
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2019 (English)In: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 116, no 30, p. 15226-15235Article in journal (Refereed) Published
Abstract [en]

The progressive accumulation, aggregation, and spread of alpha-synuclein (alpha SN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with alpha SN species, influencing its toxicity in the brain. In the present study, we extended analyses of alpha SN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that alpha SN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant alpha SN, and the subsequent uptake of prepared vesicles by human dopaminergic neuronal-like cells. Further, we report an increased level of ApoE in CSF from early PD patients compared with matched controls in 3 independent cohorts. Moreover, in contrast to controls, we observed the presence of ApoE-positive neuromelanin-containing dopaminergic neurons in substantia nigra of PD patients. In conclusion, the cooccurrence of alpha SN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for alpha SN spreading in the extracellular milieu of PD.

Place, publisher, year, edition, pages
NATL ACAD SCIENCES , 2019. Vol. 116, no 30, p. 15226-15235
Keywords [en]
apolipoproteins, alpha-synuclein, Parkinson's disease, cerebrospinal fluid
National Category
Neurology Neurosciences
Identifiers
URN: urn:nbn:se:uu:diva-391372DOI: 10.1073/pnas.1821409116ISI: 000476715500067PubMedID: 31270237OAI: oai:DiVA.org:uu-391372DiVA, id: diva2:1354208
Funder
Swedish Foundation for Strategic Research EU, European Research CouncilSwedish Research CouncilKnut and Alice Wallenberg FoundationAvailable from: 2019-09-24 Created: 2019-09-24 Last updated: 2019-09-24Bibliographically approved

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