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

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Reimer, Lasse (author)

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

Article/chapterEnglish2021

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2020-08-06
John Wiley & Sons,2021
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LIBRIS-ID:oai:DiVA.org:umu-174348
https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-174348URI
https://doi.org/10.1111/bpa.12883DOI

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Language:English
Summary in:English

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Subject category:art swepub-publicationtype

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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. Viain vitrophosphorylation 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 noncoding 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.

Subject headings and genre

MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Cell- och molekylärbiologi hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Cell and Molecular Biology hsv//eng
MEDICIN OCH HÄLSOVETENSKAP Medicinska och farmaceutiska grundvetenskaper Neurovetenskaper hsv//swe
MEDICAL AND HEALTH SCIENCES Basic Medicine Neurosciences hsv//eng
neurodegeneration
neuroinflammation
PKR
Tau
tauopathies

Added entries (persons, corporate bodies, meetings, titles ...)

Betzer, Cristine (author)
Kofoed, Rikke Hahn (author)
Volbracht, Christiane (author)
Fog, Karina (author)
Kurhade, Chaitanya,1989-Umeå universitet,Virologi,Molekylär Infektionsmedicin, Sverige (MIMS)(Swepub:umu)chku0007 (author)
Nilsson, EmmaUmeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Virologi(Swepub:umu)niem6001 (author)
Överby, Anna K.Umeå universitet,Molekylär Infektionsmedicin, Sverige (MIMS),Virologi(Swepub:umu)anaovy99 (author)
Jensen, Poul Henning (author)
Umeå universitetVirologi (creator_code:org_t)

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In:Brain Pathology: John Wiley & Sons31:1, s. 103-1191015-63051750-3639

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By the author/editor: Reimer, Lasse; Betzer, Cristine; Kofoed, Rikke Ha ...; Volbracht, Chris ...; Fog, Karina; Kurhade, Chaitan ...; show more...; Nilsson, Emma; Överby, Anna K.; Jensen, Poul Hen ...; show less...

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Cell and Molecul ...

MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Neurosciences

Articles in the publication: Brain Pathology

By the university: Umeå University

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