Three- and four-repeat tau regulate the dynamic instability of two distinct microtubule subpopulations in qualitatively different manners. Implications for neurodegeneration.

Details

Serval ID
serval:BIB_5F842C7FB357
Type
Article: article from journal or magazin.
Collection
Publications
Title
Three- and four-repeat tau regulate the dynamic instability of two distinct microtubule subpopulations in qualitatively different manners. Implications for neurodegeneration.
Journal
The Journal of biological chemistry
Author(s)
Levy S.F., Leboeuf A.C., Massie M.R., Jordan M.A., Wilson L., Feinstein S.C.
ISSN
0021-9258 (Print)
ISSN-L
0021-9258
Publication state
Published
Issued date
08/04/2005
Peer-reviewed
Oui
Volume
280
Number
14
Pages
13520-13528
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, P.H.S.
Publication Status: ppublish
Abstract
The microtubule-associated protein tau is implicated in the pathogenesis of many neurodegenerative diseases, including fronto-temporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), in which both RNA splicing and amino acid substitution mutations in tau cause dominantly inherited early onset dementia. RNA-splicing FTDP-17 mutations alter the wild-type approximately 50:50 3-repeat (3R) to 4-repeat (4R) tau isoform ratio, usually resulting in an excess of 4R tau. To examine further how splicing mutations might cause dysfunction by misregulation of microtubule dynamics, we used video microscopy to determine the in vitro behavior of individual microtubules stabilized by varying amounts of human 4R and 3R tau. At low tau:tubulin ratios (1:55 and 1:45), all 3R isoforms reduced microtubule growth rates relative to the no-tau control, whereas all 4R isoforms increased them; however, at a high tau:tubulin ratio (1:20), both 4R and 3R tau increased the growth rates. Further analysis revealed two distinct subpopulations of growing microtubules in the absence of tau. Increasing concentrations of both 4R and 3R tau resulted in an increase in the size of the faster growing subpopulation of microtubules; however, 4R tau caused a redistribution to the faster growing subpopulation at lower tau:tubulin ratios than 3R tau. This modulation of discrete growth rate subpopulations by tau suggests that tau causes a conformational shift in the microtubule resulting in altered dynamics. Quantitative and qualitative differences observed between 4R and 3R tau are consistent with a "microtubule misregulation" model in which abnormal tau isoform expression results in the inability to properly regulate microtubule dynamics, leading to neuronal death and dementia.
Keywords
Alternative Splicing, Animals, Cattle, Humans, Microtubule-Associated Proteins/genetics, Microtubule-Associated Proteins/metabolism, Microtubules/chemistry, Microtubules/metabolism, Neurodegenerative Diseases/metabolism, Protein Conformation, Protein Isoforms/chemistry, Protein Isoforms/genetics, Protein Isoforms/metabolism, Tubulin/metabolism, tau Proteins/chemistry, tau Proteins/genetics, tau Proteins/metabolism
Pubmed
Web of science
Open Access
Yes
Create date
13/10/2014 10:09
Last modification date
20/08/2019 14:17
Usage data