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Human TTBK1, TTBK2 and MARK1 kinase toxicity in Drosophila melanogaster is exacerbated by co-expression of human Tau
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Developmental Biology. Linköping University, Faculty of Medicine and Health Sciences. Airopt Sp Zoo, Poland.
Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0001-5095-541X
2017 (English)In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 6, no 7, 1013-1023 p.Article in journal (Refereed) Published
Abstract [en]

Tau protein is involved in numerous human neurodegenerative diseases, and Tau hyper-phosphorylation has been linked to Tau aggregation and toxicity. Previous studies have addressed toxicity and phospho-biology of human Tau (hTau) in Drosophila melanogaster. However, hTau transgenes have most often been randomly inserted in the genome, thus making it difficult to compare between different hTau isoforms and phospho-mutants. In addition, many studies have expressed hTau also in mitotic cells, causing nonphysiological toxic effects. Here, we overcome these confounds by integrating UAS-hTau isoform transgenes into specific genomic loci, and express hTau post-mitotically in the Drosophila nervous system. Lifespan and locomotor analyses show that all six of the hTau isoforms elicit similar toxicity in flies, although hTau(2N3R) showed somewhat elevated toxicity. To determine if Tau phosphorylation is responsible for toxicity, we analyzed the effects of co-expressing hTau isoforms together with Tau-kinases, focusing on TTBK1, TTBK2 and MARK1. We observed toxicity when expressing each of the three kinases alone, or in combination. Kinase toxicity was enhanced by hTau co-expression, with strongest co-toxicity for TTBK1. Mutagenesis and phosphorylation analysis indicates that hTau-MARK1 combinatorial toxicity may be due to direct phosphorylation of hTau, while hTau-TTBK1/2 combinatorial toxicity may result from independent toxicity mechanisms.

Place, publisher, year, edition, pages
COMPANY OF BIOLOGISTS LTD , 2017. Vol. 6, no 7, 1013-1023 p.
Keyword [en]
Tauopathy; Neuronal toxicity; Drosophila; Tau-kinases
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-139556DOI: 10.1242/bio.022749ISI: 000405569500010PubMedID: 28711868OAI: oai:DiVA.org:liu-139556DiVA: diva2:1130115
Note

Funding Agencies|Konung Gustaf V: s och Drottning Victorias Frimurarestiftelse [700-0557]

Available from: 2017-08-08 Created: 2017-08-08 Last updated: 2017-08-29

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