Poul Henning Jensen

PKR kinase directly regulates tau expression and Alzheimer's Disease-related tau phosphorylation

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

DOI

  • Lasse Reimer
  • Cristine Betzer
  • Rikke Hahn Kofoed, Danish Research Institute of Translational Neuroscience DANDRITE
  • ,
  • Christiane Volbracht, Hospital Lillebaelt, Middelfart, Denmark, University of Southern Denmark, Odense, Denmark, and Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Karina Fog, Hospital Lillebaelt, Middelfart, Denmark, University of Southern Denmark, Odense, Denmark, and Aarhus University Hospital, Aarhus, Denmark.
  • ,
  • Chaitanya Kurhade, Umeå University
  • ,
  • Emma Nilsson, Umeå University
  • ,
  • Anna K Överby, Umeå University
  • ,
  • Poul Henning Jensen

Deposition of extensively hyperphosphorylated tau in specific brain cells is a clear pathological hallmark in Alzheimer's disease and a number of other neurodegenerative disorders, collectively termed the tauopathies. Furthermore, hyperphosphorylation of tau prevents it from fulfilling its physiological role as a microtubule-stabilizing protein and leaves it increasingly vulnerable to self-assembly, suggestive of a central underlying role of hyperphosphorylation as a contributing factor in the etiology of these diseases. Via in vitro phosphorylation and regulation of kinase activity within cells and acute brain tissue, we reveal that the inflammation associated kinase, protein kinase R (PKR), directly phosphorylates numerous abnormal and disease-modifying residues within tau including Thr181, Ser199/202, Thr231, Ser262, Ser396, Ser404 and Ser409. Similar to disease processes, these PKR-mediated phosphorylations actively displace tau from microtubules in cells. In addition, PKR overexpression and knockdown, respectively, increase and decrease tau protein and mRNA levels in cells. This regulation occurs independent of non-coding transcriptional elements, suggesting an underlying mechanism involving intra-exonic regulation of the tau-encoding microtubule-associated protein tau (MAPT) gene. Finally, acute encephalopathy in wild type mice, induced by intracranial Langat virus infection, results in robust inflammation and PKR upregulation accompanied by abnormally phosphorylated full-length- and truncated tau. These findings indicate that PKR, independent of other kinases, and upon acute brain inflammation, is capable of triggering pathological modulation of tau, which in turn, might form the initial pathologic seed in several tauopathies such as Alzheimer's disease and Chronic traumatic encephalopathy where inflammation is severe.

Original languageEnglish
JournalBrain Pathology
ISSN1015-6305
DOIs
Publication statusE-pub ahead of print - 27 Jul 2020

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