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

TY - JOUR

T1 - PKR kinase directly regulates tau expression and Alzheimer's Disease-related tau phosphorylation

AU - Reimer, Lasse

AU - Betzer, Cristine

AU - Kofoed, Rikke Hahn

AU - Volbracht, Christiane

AU - Fog, Karina

AU - Kurhade, Chaitanya

AU - Nilsson, Emma

AU - Överby, Anna K

AU - Jensen, Poul Henning

N1 - This article is protected by copyright. All rights reserved.

PY - 2021/1

Y1 - 2021/1

N2 - 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.

AB - 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.

KW - ACTIVATION

KW - ALPHA-SYNUCLEIN

KW - DEGENERATION

KW - DEPENDENT PROTEIN-KINASE

KW - IFN

KW - INTERFERON

KW - MEMORY IMPAIRMENT

KW - PKR

KW - TANGLES

KW - TAUOPATHY

KW - TNF-ALPHA

KW - Tau

KW - neurodegeneration

KW - neuroinflammation

KW - tauopathies

UR - http://www.scopus.com/inward/record.url?scp=85089091967&partnerID=8YFLogxK

U2 - 10.1111/bpa.12883

DO - 10.1111/bpa.12883

M3 - Journal article

C2 - 32716602

SN - 1015-6305

VL - 31

SP - 103

EP - 119

JO - Brain Pathology

JF - Brain Pathology

IS - 1

ER -