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Gene Expression of Quaking in Sporadic Alzheimer’s Disease Patients is Both Upregulated and Related to Expression Levels of Genes Involved in Amyloid Plaque and Neurofibrillary Tangle Formation
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.ORCID iD: 0000-0003-3459-0451
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
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2016 (English)In: Journal of Alzheimer's Disease, ISSN 1387-2877, E-ISSN 1875-8908, Vol. 53, no 1, 209-219 p.Article in journal (Refereed) Published
Abstract [en]

Quaking (QKI) is a gene exclusively expressed within glial cells. QKI has previously been implicated in various neurological disorders and diseases, including Alzheimer’s disease (AD), a condition for which increasing evidence suggests a central role of glia cells. The objective of the present study was to investigate the expression levels of QKI and three QKI isoforms (QKI5, QKI6, and QKI7) in AD. Genes that have previously been related to the ontogeny and progression of AD, specifically APP, PSEN1, PSEN2, and MAPT, were also investigated. A real-time PCR assay of 123 samples from human postmortem sporadic AD patients and control brains was performed. The expression values were analyzed with an analysis of covariance model and subsequent multiple regressions to explore the possibility of related expression values between QKI, QKI isoforms, and AD-related genes. Further, the sequences of AD-related genes were analyzed for the presence of QKI binding domains. QKI and all measured QKI isoforms were found to be significantly upregulated in AD samples, relative to control samples. However, APP, PSEN1, PSEN2, and MAPT were not found to be significantly different. QKI and QKI isoforms were found to be predictive for the variance of APP, PSEN1, PSEN2, and MAPT, and putative QKI binding sites suggests an interaction with QKI. Overall, these results implicate a possible role of QKI in AD, although the exact mechanism by which this occurs remains to be uncovered.

Place, publisher, year, edition, pages
IOS Press, 2016. Vol. 53, no 1, 209-219 p.
Keyword [en]
Amyloid-beta, APP, gene expression, glia, MAPT, neurodegenerative diseases, real-time polymerase chain reaction, PSEN1, PSEN2
National Category
Genetics Neurosciences
URN: urn:nbn:se:uu:diva-286589DOI: 10.3233/JAD-160160ISI: 000379742200019PubMedID: 27163826OAI: diva2:921832
Göran Gustafsson Foundation for promotion of scientific research at Uppala University and Royal Institute of TechnologyTorsten Söderbergs stiftelseSwedish Society of MedicineMagnus Bergvall FoundationLars Hierta Memorial FoundationEU, FP7, Seventh Framework Programme, 608743The Swedish Brain Foundation
Available from: 2016-04-21 Created: 2016-04-21 Last updated: 2016-11-25Bibliographically approved
In thesis
1. Translational research of the quaking gene: Focusing on the conjunction between development and disease
Open this publication in new window or tab >>Translational research of the quaking gene: Focusing on the conjunction between development and disease
2016 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Quaking (QKI) is an RNA binding protein involved in the post-transcriptional regulation of gene expression. Originally identified as the cause of hypomyelination in a mouse mutant, it has since been consistently implicated in a wide range of neurological diseases. As a gene exclusively expressed in glial cells of the central nervous system, such associations emphasise the importance of an indirect, or non-neuronal link to aberrant neural function. A role in early neural development has also been suggested from the viable and embryonic lethal mouse mutants, yet detailed and in vivo study has been precluded thus far by the murine uterine gestation, and mutant lethality prior to oligodendrogenesis. This thesis examines the role of QKI in human neurological disease, and explores the use of the zebrafish as a model organism to allow the unimpeded study of neural development.

We first examined the expression of QKI in human post-mortem brain samples, in separate studies of Alzheimer’s disease (AD) and schizophrenia. In AD we found that QKI and the splice variants QKI5, QKI6, and QKI7 were all significantly upregulated, and were additionally implicated in the regulation of genes related to AD pathogenesis. Within schizophrenic samples, we explored the expression of QKI6B, a newly identified splice variant of QKI, alongside GFAP. We found that both were significantly upregulated, and a previously implicated regulation of GFAP by QKI was supported. In order to advance investigations of the potential of QKI to disturb neural development, we established the suitability of zebrafish for studying qki. This was achieved through phylogenetic and syntenic analysis, coupled with examination of the qki genes expression patterns. We found that qkib and qki2 are orthologues of human QKI, and both have distinct, yet overlapping expression patterns in neural progenitors, and are not found in differentiated neurons. Following from this, we explored the effects of knockdown to qkib and qki2, finding that qkib exclusively led to aberrant motor neuron development, cerebellar abnormalities, and alterations to the progenitor domain. This clearly demonstrated the crucial role of qki in early neural development, and confirms a previously speculated, yet occluded, function prior to oligodendrogenesis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2016. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1381
QKI, glia, oligodendrocyte, Alzheimer's, schizophrenia, zebrafish, statistics, morpholino
National Category
Genetics Developmental Biology Neurosciences
Research subject
Biology with specialization in Evolutionary Organismal Biology
urn:nbn:se:uu:diva-287408 (URN)978-91-554-9595-4 (ISBN)
Public defence
2016-06-14, Zootisalen, EBC, Norbyvägen 18A, Uppsala, 13:00 (English)
Available from: 2016-05-17 Created: 2016-04-24 Last updated: 2016-06-01

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Farnsworth, BrynPeuckert, ChristianeJazin, ElenaEmilsson Sors, Lina
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