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Proc Natl Acad Sci U S A. 2019 Jul 23;116(30):15226-15235. doi: 10.1073/pnas.1821409116. Epub 2019 Jul 3.

α-synuclein-lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson's disease patients.

Author information

1
Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institute, 171 76 Stockholm, Sweden.
2
Biomolecular Mass Spectrometry Imaging, National Resource for Mass Spectrometry Imaging, Science for Life Laboratory, Department of Pharmaceutical Biosciences, Uppsala University, SE-75124 Uppsala, Sweden.
3
Clinical Memory Research Unit, Faculty of Medicine, Lund University, 221 00 Lund, Sweden.
4
Memory Clinic, Skåne University Hospital, 205 02 Malmö, Sweden.
5
Department of Pharmacology and Clinical Neuroscience, Umeå University, 901 87 Umeå, Sweden.
6
Department of Clinical Neuroscience, Neuro Svenningsson, Karolinska Institute, 171 76 Stockholm, Sweden; Per.Svenningsson@ki.se.

Abstract

The progressive accumulation, aggregation, and spread of α-synuclein (αSN) are common hallmarks of Parkinson's disease (PD) pathology. Moreover, numerous proteins interact with αSN species, influencing its toxicity in the brain. In the present study, we extended analyses of αSN-interacting proteins to cerebrospinal fluid (CSF). Using coimmunoprecipitation, followed by mass spectrometry, we found that αSN colocalize with apolipoproteins on lipoprotein vesicles. We confirmed these interactions using several methods, including the enrichment of lipoproteins with a recombinant αSN, 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 αSN on lipoprotein vesicles, and their uptake by dopaminergic neurons along with an increase of ApoE in early PD, proposes a mechanism(s) for αSN spreading in the extracellular milieu of PD.

KEYWORDS:

Parkinson's disease; apolipoproteins; cerebrospinal fluid; α-synuclein

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