Header

UZH-Logo

Maintenance Infos

Protein phosphatase 2A in Alzheimer’s disease pathogenesis, memory and development


Schild, A. Protein phosphatase 2A in Alzheimer’s disease pathogenesis, memory and development. 2005, University of Zurich, Faculty of Science.

Abstract

In both, Alzheimer's disease (AD) and frontotemporal dementia (FTD), potein tau is hyperphosphorylated, detaches from the microtubules and forms filaments. Tau is a substrate of protein phosphatase 2A (PP2A). PP2A is a family of heterotrimeric enzymes with diverse functions under physiologic and pathologic conditions. In brains of AD patients, mRNA levels of individual subunits of PP2A have been found to be reduced and to affect PP2A activity, which correlated with tangle load. Since specific inhibition of PP2A in vivo is not possible chemically, we have designed dominant negative transgenic mouse models with altered PP2A composition and/or activity, by overexpression of the mutant catalytic subunits L199P and L309A. Leucine 199 of the catalytic subunit C? is in the catalytic core while the carboxyterminal leucine 309 plays
a crucial role in the recruitment of regulatory subunits into the complex in vitro, a process that determines substrate specificity of PP2A. Our novel transgenic mouse
models, together with the consolidated findings from the present studies on the distribution of PR55/B subunits and their abundance in mice and human cell lines, provide valuable tools to study the role of PR55/B regulatory subunits in PP2A specificity and activity. Our results have thereby facilitated the development and analysis of in vivo models of PP2A function in the brain, have contributed to the understanding of PP2A composition and specificity as well as the development of the lacrimal system, and have further revealed an involvement of PP2A activity in memory
retrieval of mice.

Abstract

In both, Alzheimer's disease (AD) and frontotemporal dementia (FTD), potein tau is hyperphosphorylated, detaches from the microtubules and forms filaments. Tau is a substrate of protein phosphatase 2A (PP2A). PP2A is a family of heterotrimeric enzymes with diverse functions under physiologic and pathologic conditions. In brains of AD patients, mRNA levels of individual subunits of PP2A have been found to be reduced and to affect PP2A activity, which correlated with tangle load. Since specific inhibition of PP2A in vivo is not possible chemically, we have designed dominant negative transgenic mouse models with altered PP2A composition and/or activity, by overexpression of the mutant catalytic subunits L199P and L309A. Leucine 199 of the catalytic subunit C? is in the catalytic core while the carboxyterminal leucine 309 plays
a crucial role in the recruitment of regulatory subunits into the complex in vitro, a process that determines substrate specificity of PP2A. Our novel transgenic mouse
models, together with the consolidated findings from the present studies on the distribution of PR55/B subunits and their abundance in mice and human cell lines, provide valuable tools to study the role of PR55/B regulatory subunits in PP2A specificity and activity. Our results have thereby facilitated the development and analysis of in vivo models of PP2A function in the brain, have contributed to the understanding of PP2A composition and specificity as well as the development of the lacrimal system, and have further revealed an involvement of PP2A activity in memory
retrieval of mice.

Statistics

Downloads

873 downloads since deposited on 07 Sep 2011
154 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Dissertation
Referees:Sonderegger P, Götz J, Nitsch R M
Communities & Collections:04 Faculty of Medicine > Institute for Regenerative Medicine (IREM)
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2005
Deposited On:07 Sep 2011 10:54
Last Modified:16 Aug 2016 10:14
Number of Pages:129
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005026632

Download

Preview Icon on Download
Preview
Content: Published Version
Filetype: PDF
Size: 12MB

Article Networks

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations