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

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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; Hansson, Oskar; Forsgren, Lars; Andrén, Per E.; Svenningsson, Per.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 116, No. 30, 23.07.2019, p. 15226-15235.

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Paslawski, Wojciech ; Zareba-Paslawska, Justyna ; Zhang, Xiaoqun ; Hölzl, Katharina ; Wadensten, Henrik ; Shariatgorji, Mohammadreza ; Janelidze, Shorena ; Hansson, Oskar ; Forsgren, Lars ; Andrén, Per E. ; Svenningsson, Per. / α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients. In: Proceedings of the National Academy of Sciences of the United States of America. 2019 ; Vol. 116, No. 30. pp. 15226-15235.

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TY - JOUR

T1 - α-synuclein−lipoprotein interactions and elevated ApoE level in cerebrospinal fluid from Parkinson’s disease patients

AU - Paslawski, Wojciech

AU - Zareba-Paslawska, Justyna

AU - Zhang, Xiaoqun

AU - Hölzl, Katharina

AU - Wadensten, Henrik

AU - Shariatgorji, Mohammadreza

AU - Janelidze, Shorena

AU - Hansson, Oskar

AU - Forsgren, Lars

AU - Andrén, Per E.

AU - Svenningsson, Per

PY - 2019/7/23

Y1 - 2019/7/23

N2 - 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.

AB - 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.

KW - Apolipoproteins

KW - Cerebrospinal fluid

KW - Parkinson’s disease

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85069630591&partnerID=8YFLogxK

U2 - 10.1073/pnas.1821409116

DO - 10.1073/pnas.1821409116

M3 - Article

VL - 116

SP - 15226

EP - 15235

JO - Proceedings of the National Academy of Sciences

JF - Proceedings of the National Academy of Sciences

SN - 1091-6490

IS - 30

ER -