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

Research output: Contribution to journalArticle

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.

Details

Authors
  • Wojciech Paslawski
  • Justyna Zareba-Paslawska
  • Xiaoqun Zhang
  • Katharina Hölzl
  • Henrik Wadensten
  • Mohammadreza Shariatgorji
  • Shorena Janelidze
  • Oskar Hansson
  • Lars Forsgren
  • Per E. Andrén
  • Per Svenningsson
Organisations
External organisations
  • Karolinska Institutet
  • Uppsala University
  • Skåne University Hospital
  • Umeå University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Neurology

Keywords

  • Apolipoproteins, Cerebrospinal fluid, Parkinson’s disease, α-synuclein
Original languageEnglish
Pages (from-to)15226-15235
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number30
Publication statusPublished - 2019 Jul 23
Publication categoryResearch
Peer-reviewedYes