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Low mRNA levels of RGS4 splice variants in Alzheimer’s disease and association between a rare haplotype and decreased mRNA expression
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (beteende genetik)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics. (beteende genetik)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Animal Development and Genetics.
2006 (English)In: Synapse, ISSN 0887-4476, E-ISSN 1098-2396, Vol. 59, no 3, 173-176 p.Article in journal (Refereed) Published
Abstract [en]

Regulator of G-protein signaling 4 (RGS4) showed decreased mRNAlevels in Alzheimer’s disease in a large collection of human brain autopsies from prefrontalcortex. The expression levels of three RGS4 splice variants were examined inthe same samples, and the association between RGS4 gene expression and/or the diseasewith single nucleotide polymorphisms located in this gene was explored. We showthat all splice variants are down-regulated in patients. We also demonstrate that onerare haplotype (ATAG) is associated with decreased mRNA levels in both cases andcontrols. Our results suggest that an altered regulation in transcription initiation maybe an important mechanism for low RGS4 protein levels in Alzeimer’s disease.

Place, publisher, year, edition, pages
2006. Vol. 59, no 3, 173-176 p.
Keyword [en]
neurodegeneration, RGS splice variants, SNP, real-time RT-PCR
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-93408DOI: 10.1002/SYN.20226PubMedID: 16358332OAI: oai:DiVA.org:uu-93408DiVA: diva2:166872
Available from: 2005-09-08 Created: 2005-09-08 Last updated: 2010-03-29Bibliographically approved
In thesis
1. Detection of Differentially Expressed Genes in Alzheimer's Disease: Regulator of G-protein Signalling 4: A Novel Mediator of APP Processing
Open this publication in new window or tab >>Detection of Differentially Expressed Genes in Alzheimer's Disease: Regulator of G-protein Signalling 4: A Novel Mediator of APP Processing
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Alzheimer’s disease is a neurodegenerative disease characterised by progressive memory deterioration and cognitive impairment. Pathological hallmarks are extracellular senile plaques, neurofibrillary tangles and neuron loss. Senile plaques are produced through altered processing of the membrane-bound protein APP. Different neurotransmitter signal transduction pathways have been implicated in the formation or development of Alzheimer’s pathologies, but the molecular mechanisms behind these changes are not well known.

The overall aims of this thesis were to identify novel genes with differential expression in Alzheimer’s disease and to investigate mechanisms initiating these changes and their relationship to the disease. A real-time RT-PCR strategy was developed to enable detection of small mRNA changes in human brain autopsy samples. This approach was first used to investigate levels of expression of a candidate gene (MAO), and later employed to verify gene expression differences detected by cDNA microarray analysis. Of several genes verified as differentially expressed in the patients, ITPKB (Inositol 1,4,5-trisphosphate 3-kinase B) and RGS4 (Regulator of G-protein signalling 4) presented the largest expression differences in Alzheimer’s cases compared to control samples. Several splice variants of RGS4 showed similar down-regulation levels and one rare haplotype was associated with decreased RGS4 expression. Functional studies in SH-SY5Y cell cultures overexpressing RGS4 showed that it is likely that RGS4 affects APP processing by regulating PRKC expression levels.

The combined expression of RGS4 and ITPKB is for the first time presented in this thesis as genes with altered mRNA levels in Alzheimer’s disease. These two genes are implicated in the same signalling pathway that modifies calcium levels in the cell. Furthermore, the fact that RGS4 affects APP processing suggests that RGS4 is involved in the development of senile plaques. This motivates further functional studies of this gene and suggests that RGS4 may become a new potential drug target for Alzheimer’s disease.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 52 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 85
Keyword
Alzheimer's disease, RGS4, ITPKB, RAB3A, APP processinig
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-5910 (URN)91-554-6234-X (ISBN)
Public defence
2005-09-29, Ekman-salen, Norby vägen, EBC, 09:15 (English)
Opponent
Supervisors
Available from: 2005-09-08 Created: 2005-09-08 Last updated: 2010-02-08Bibliographically approved

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Jazin, Elena

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