Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death

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Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death. / Reimer, Lasse; Lund, Louise Buur; Betzer, Cristine; Zheng, Jin; Nielsen, Lærke Dalsgaard; Kofoed, Rikke Hahn; Lassen, Louise Berkhoudt; Bølcho, Ulrik; Paludan, Søren Riis; Fog, Karina; Jensen, Poul Henning.

In: Neurobiology of Disease, 01.05.2018.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

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@article{1c96923e054b4583a83c1e01a9d59a7a,
title = "Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death",
abstract = "Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated α-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration. In vitro phosphorylation demonstrates that PKR can directly bind and phosphorylate monomeric and filamenteous α-synuclein on Ser129. Inhibition and knockdown of PKR reduce Ser129 phosphorylation in different models (SH-SY5Y ASYN cells, OLN-AS7 cells, primary mouse hippocampal neurons, and acute brain slices), while overexpression of constitutively active PKR increases Ser129 α-syn phosphorylation. Treatment with pre-formed α-synuclein fibrils, proteostatic stress-promoting MG-132 and known PKR activators, herpes simplex virus-1-∆ICP34.5 and LPS, as well as PKR inducer, IFN-β-1b, lead to increased levels of phosphorylated Ser129 α-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of α-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of α-synuclein.",
author = "Lasse Reimer and Lund, {Louise Buur} and Cristine Betzer and Jin Zheng and Nielsen, {L{\ae}rke Dalsgaard} and Kofoed, {Rikke Hahn} and Lassen, {Louise Berkhoudt} and Ulrik B{\o}lcho and Paludan, {S{\o}ren Riis} and Karina Fog and Jensen, {Poul Henning}",
note = "Copyright {\circledC} 2017. Published by Elsevier Inc.",
year = "2018",
month = "5",
day = "1",
doi = "10.1016/j.nbd.2018.03.001",
language = "English",
journal = "Neurobiology of Disease",
issn = "0969-9961",
publisher = "Academic Press",

}

RIS

TY - JOUR

T1 - Inflammation kinase PKR phosphorylates α-synuclein and causes α-synuclein-dependent cell death

AU - Reimer, Lasse

AU - Lund, Louise Buur

AU - Betzer, Cristine

AU - Zheng, Jin

AU - Nielsen, Lærke Dalsgaard

AU - Kofoed, Rikke Hahn

AU - Lassen, Louise Berkhoudt

AU - Bølcho, Ulrik

AU - Paludan, Søren Riis

AU - Fog, Karina

AU - Jensen, Poul Henning

N1 - Copyright © 2017. Published by Elsevier Inc.

PY - 2018/5/1

Y1 - 2018/5/1

N2 - Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated α-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration. In vitro phosphorylation demonstrates that PKR can directly bind and phosphorylate monomeric and filamenteous α-synuclein on Ser129. Inhibition and knockdown of PKR reduce Ser129 phosphorylation in different models (SH-SY5Y ASYN cells, OLN-AS7 cells, primary mouse hippocampal neurons, and acute brain slices), while overexpression of constitutively active PKR increases Ser129 α-syn phosphorylation. Treatment with pre-formed α-synuclein fibrils, proteostatic stress-promoting MG-132 and known PKR activators, herpes simplex virus-1-∆ICP34.5 and LPS, as well as PKR inducer, IFN-β-1b, lead to increased levels of phosphorylated Ser129 α-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of α-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of α-synuclein.

AB - Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy comprise a group of neurodegenerative diseases termed synucleinopathies. Synucleinopathie are, characterized by presence of inclusion bodies in degenerating brain cells which contain aggregated α-synuclein phosphorylated on Ser129. Although the inflammation-associated serine-threonine kinase, PKR (EIF2AK2), promotes cellular protection against infection, we demonstrate a pro-degenerative role of activated PKR in an α-synuclein-dependent cell model of multiple system atrophy, where inhibition and silencing of PKR decrease cellular degeneration. In vitro phosphorylation demonstrates that PKR can directly bind and phosphorylate monomeric and filamenteous α-synuclein on Ser129. Inhibition and knockdown of PKR reduce Ser129 phosphorylation in different models (SH-SY5Y ASYN cells, OLN-AS7 cells, primary mouse hippocampal neurons, and acute brain slices), while overexpression of constitutively active PKR increases Ser129 α-syn phosphorylation. Treatment with pre-formed α-synuclein fibrils, proteostatic stress-promoting MG-132 and known PKR activators, herpes simplex virus-1-∆ICP34.5 and LPS, as well as PKR inducer, IFN-β-1b, lead to increased levels of phosphorylated Ser129 α-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of α-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of α-synuclein.

U2 - 10.1016/j.nbd.2018.03.001

DO - 10.1016/j.nbd.2018.03.001

M3 - Journal article

C2 - 29501855

JO - Neurobiology of Disease

JF - Neurobiology of Disease

SN - 0969-9961

ER -