Three repeat isoforms of tau inhibit assembly of four repeat tau filaments

Stephanie J. Adams, Michael Deture, Melinda McBride, Dennis W Dickson, Leonard Petrucelli

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Tauopathies are defined by assembly of the microtubule associated protein tau into filamentous tangles and classified by the predominant tau isoform within these aggregates. The major isoforms are determined by alternative mRNA splicing of exon 10 generating tau with three (3R) or four (4R) ~32 amino acid imperfect repeats in the microtubule binding domain. In normal adult brains there is an approximately equimolar ratio of 3R and 4R tau which is altered by several disease-causing mutations in the tau gene. We hypothesized that when 4R and 3R tau isoforms are not at equimolar ratios aggregation is favored. Here we provide evidence for the first time that the combination of 3R and 4R tau isoforms results in less in vitro heparin induced polymerization than with 4R preparations alone. This effect was independent of reducing conditions and the presence of alternatively spliced exons 2 and 3 N-terminal inserts. The addition of even small amounts of 3R to 4R tau assembly reactions significantly decreased 4R assembly. Together these findings suggest that co-expression of 3R and 4R tau isoforms reduce tau filament assembly and that 3R tau isoforms inhibit 4R tau assembly. Expression of equimolar amounts of 3R and 4R tau in adult humans may be necessary to maintain proper neuronal microtubule dynamics and to prevent abnormal tau filament assembly. Importantly, these findings indicate that disruption of the normal equimolar 3R to 4R ratio may be sufficient to drive tau aggregation and that restoration of the tau isoform balance may have important therapeutic implications in tauopathies.

Original languageEnglish (US)
Article numbere10810
JournalPLoS One
Volume5
Issue number5
DOIs
StatePublished - 2010

Fingerprint

microtubules
Protein Isoforms
exons
Tauopathies
alternative splicing
heparin
protein aggregates
polymerization
Microtubules
Exons
Agglomeration
mutation
brain
therapeutics
amino acids
Microtubule-Associated Proteins
Alternative Splicing
Polymerization
genes
Restoration

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Three repeat isoforms of tau inhibit assembly of four repeat tau filaments. / Adams, Stephanie J.; Deture, Michael; McBride, Melinda; Dickson, Dennis W; Petrucelli, Leonard.

In: PLoS One, Vol. 5, No. 5, e10810, 2010.

Research output: Contribution to journalArticle

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