| First Author | Reimer L | Year | 2018 |
| Journal | Neurobiol Dis | Volume | 115 |
| Pages | 17-28 | PubMed ID | 29501855 |
| Mgi Jnum | J:268466 | Mgi Id | MGI:6267132 |
| Doi | 10.1016/j.nbd.2018.03.001 | Citation | Reimer L, et al. (2018) Inflammation kinase PKR phosphorylates alpha-synuclein and causes alpha-synuclein-dependent cell death. Neurobiol Dis 115:17-28 |
| abstractText | 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 alpha-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 alpha-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 alpha-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 alpha-syn phosphorylation. Treatment with pre-formed alpha-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-beta-1b, lead to increased levels of phosphorylated Ser129 alpha-synuclein that is completely blocked by simultaneous PKR inhibition. These results reveal a direct link between PKR and the phosphorylation and toxicity of alpha-synuclein, and they support that neuroinflammatory processes play a role in modulating the pathogenicity of alpha-synuclein. |
