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

Paslawski, Wojciech; Zareba-Paslawska, Justyna; Zhang, Xiaoqun; Hölzl, Katharina; Wadensten, Henrik; Shariatgorji, Mohammadreza; Janelidze, Shorena LU ; Hansson, Oskar LU ; Forsgren, Lars and Andrén, Per E., et al. (2019) In Proceedings of the National Academy of Sciences of the United States of America 116(30). p.15226-15235
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... (More)

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.

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publication status
published
subject
keywords
Apolipoproteins, Cerebrospinal fluid, Parkinson’s disease, α-synuclein
in
Proceedings of the National Academy of Sciences of the United States of America
volume
116
issue
30
pages
10 pages
publisher
National Acad Sciences
external identifiers
  • scopus:85069630591
ISSN
0027-8424
DOI
10.1073/pnas.1821409116
language
English
LU publication?
yes
id
750fec8c-b324-4919-973c-c70911fb13d8
date added to LUP
2019-08-29 13:49:37
date last changed
2019-08-30 03:00:03
@article{750fec8c-b324-4919-973c-c70911fb13d8,
  abstract     = {<p>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.</p>},
  author       = {Paslawski, Wojciech and Zareba-Paslawska, Justyna and Zhang, Xiaoqun and Hölzl, Katharina and Wadensten, Henrik and Shariatgorji, Mohammadreza and Janelidze, Shorena and Hansson, Oskar and Forsgren, Lars and Andrén, Per E. and Svenningsson, Per},
  issn         = {0027-8424},
  keyword      = {Apolipoproteins,Cerebrospinal fluid,Parkinson’s disease,α-synuclein},
  language     = {eng},
  month        = {07},
  number       = {30},
  pages        = {15226--15235},
  publisher    = {National Acad Sciences},
  series       = {Proceedings of the National Academy of Sciences of the United States of America},
  title        = {α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients},
  url          = {http://dx.doi.org/10.1073/pnas.1821409116},
  volume       = {116},
  year         = {2019},
}