Abstract/Details

Transglutaminase-catalyzed cross -linking of mutant and wild-type tau protein in transgenic mice and cell culture


2004 2004

Other formats: Order a copy

Abstract (summary)

Tauopathies are a group of neurodegenerative disorders, including Alzheimer's disease and progressive supranuclear palsy, that have abnormal aggregation of hyperphosphorylated tau protein into insoluble paired helical filaments (PHF) and neurofibrillary tangles (NFT). The purpose of this dissertation was to characterize and develop animal and cell culture models to investigate the role of transglutaminase in PHF and NFT formation.

Transgenic mice that over-express the P301L tau mutation develop NFT in the hindbrain and spinal cord and exhibit dramatic motor dysfunction. We found transglutaminase-catalyzed cross-links in hyperphosphorylated tau protein from the hindbrain of P301L tau transgenic mice but not in tau protein from mice over-expressing wild-type tau or non-transgenic mice. The cross-linked, hyperphosphorylated tau protein from P301L tau mice ran at molecular weights consistent with tau aggregation. Co-localization of hyperphosphorylated tau protein and the transglutaminase-catalyzed cross-link was found in the hindbrain and spinal cord of P301L tau transgenic mice. In the spinal cord of P301L tau transgenic mice, there was an 87% co-localization of the transglutaminase-catalyzed cross-link with hyperphosphorylated tau protein. These results further suggest a role for trans glutaminase in tau aggregation and indicate that P301L transgenic mice are an excellent model to determine the involvement of transglutaminase in PHF/NFT formation. In cell culture we transiently and stably over-expressed mutant or wild-type tau protein along with transient transfection of transglutaminase in numerous cell lines. This did not result in transglutaminase-catalyzed cross-linking of tau. Thus, we generated stable cell lines in which mutant and wild-type tau expression was under the control of tetracycline. The goal was to achieve high tau expression levels that would saturate microtubules, resulting in free cytoplasmic tau that would then be available for transglutaminase cross-linking. We did not detect transglutaminase-catalyzed cross-linking of tau protein after seven, nine, or fourteen days of tau induction with transient transfection of transglutaminase. Transfection of transglutaminase also did not affect tau solubility. It does not appear that tau protein is a direct substrate of transglutaminase. The transglutaminase-catalyzed cross-linking of tau protein detected in tauopathies and P301L tau transgenic mice may be due to cross-linking of a post-translational modification on tau or a NFT-associated protein.

Indexing (details)


Subject
Neurology;
Molecular biology;
Pathology
Classification
0317: Neurology
0307: Molecular biology
0571: Pathology
Identifier / keyword
Health and environmental sciences; Biological sciences; Alzheimer's disease; Cross-linking; Tau; Transglutaminase-catalyzed
Title
Transglutaminase-catalyzed cross -linking of mutant and wild-type tau protein in transgenic mice and cell culture
Author
Halverson, Robyn A.
Number of pages
114
Publication year
2004
Degree date
2004
School code
0112
Source
DAI-B 66/02, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
ISBN
9780542012358, 0542012359
Advisor
Muma, Nancy A.
University/institution
Loyola University Chicago
University location
United States -- Illinois
Degree
Ph.D.
Source type
Dissertations & Theses
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
3165918
ProQuest document ID
305172527
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
http://search.proquest.com/docview/305172527
Access the complete full text

You can get the full text of this document if it is part of your institution's ProQuest subscription.

Try one of the following:

  • Connect to ProQuest through your library network and search for the document from there.
  • Request the document from your library.
  • Go to the ProQuest login page and enter a ProQuest or My Research username / password.