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Neurobiol Dis. 2018 Jul;115:17-28. doi: 10.1016/j.nbd.2018.03.001. Epub 2018 Mar 1.

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

Author information

1
Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Denmark; Department of Biomedicine, Aarhus University, Denmark. Electronic address: lasse.reimer@dandrite.au.dk.
2
H. Lundbeck A/S, Valby, Denmark.
3
Danish Research Institute of Translational Neuroscience - DANDRITE, Aarhus University, Denmark; Department of Biomedicine, Aarhus University, Denmark.
4
Department of Biomedicine, Aarhus University, Denmark.

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.

KEYWORDS:

Alpha-Synuclein; Cytotoxicity; EIF2AK2; Neurodegeneration; PKR; Phosphorylation; Synucleinopathies

PMID:
29501855
DOI:
10.1016/j.nbd.2018.03.001

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