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

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...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 116; no. 30; pp. 15226 - 15235
Main Authors:	Paslawskia, Wojciech, Zareba-Paslawskaa, Justyna, Zhanga, Xiaoqun, Hölzla, Katharina, Wadensten, Henrik, Shariatgorji, Mohammadreza, Janelidze, Shorena, Hansson, Oskar, Forsgren, Lars, Andrén, Per E., Svenningsson, Per
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 23-07-2019
Series:	PNAS Plus
Subjects:	Aged alpha-synuclein alpha-Synuclein - cerebrospinal fluid alpha-Synuclein - genetics Amino Acid Sequence Apolipoprotein E Apolipoproteins Apolipoproteins - cerebrospinal fluid Apolipoproteins - genetics Apolipoproteins E - cerebrospinal fluid Apolipoproteins E - genetics Biological Sciences Brain Case-Control Studies Cerebrospinal fluid Clinical Medicine Cohort Studies Dopamine receptors Dopaminergic Neurons - metabolism Dopaminergic Neurons - pathology Female Gene Expression Humans Klinisk medicin Lipoproteins Male Mass spectrometry Mass spectroscopy Medical and Health Sciences Medicin och hälsovetenskap Melanins - cerebrospinal fluid Melanins - genetics Middle Aged Movement disorders Neurodegenerative diseases Neurologi Neurology Neurons Neurotoxicity Parkinson Disease - cerebrospinal fluid Parkinson Disease - genetics Parkinson Disease - pathology Parkinson's disease PNAS Plus Protein Binding Protein Transport Proteins Sequence Alignment Sequence Homology, Amino Acid Substantia nigra Substantia Nigra - metabolism Substantia Nigra - pathology Synuclein Toxicity Transport Vesicles - metabolism Vesicles α-synuclein apolipoproteins Parkinson's disease α-synuclein cerebrospinal fluid
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by Anders Björklund, Lund University, Lund, Sweden, and approved June 10, 2019 (received for review December 18, 2018) 1W.P. and J.Z.-P. contributed equally to this work. Author contributions: W.P., J.Z.-P., O.H., L.F., P.E.A., and P.S. designed research; W.P., J.Z.-P., X.Z., K.H., H.W., M.S., S.J., O.H., L.F., P.E.A., and P.S. performed research; O.H., L.F., P.E.A., and P.S. contributed new reagents/analytic tools; W.P., J.Z.-P., and P.S. analyzed data; and W.P., J.Z.-P., X.Z., K.H., H.W., M.S., S.J., O.H., L.F., P.E.A., and P.S. wrote the paper.
ISSN:	0027-8424 1091-6490 1091-6490
DOI:	10.1073/pnas.1821409116