title: Tau protein is cross-linked by transglutaminase in P301L tau transgenic mice.
abstract: The microtubule-associated protein tau is highly soluble under physiological conditions. However, in tauopathies, tau protein aggregates into insoluble filaments and neurofibrillary tangles (NFTs). The mechanisms underlying the formation of tau filaments and NFTs in tauopathies remain unclear. Several lines of evidence suggest that transglutaminase may cross-link tau into stable, insoluble aggregates, leading to the formation of NFTs in Alzheimer's disease and progressive supranuclear palsy. To further determine the contribution of transglutaminase in the formation of NFTs, we compared the levels of cross-linked tau protein from P301L tau transgenic mice that develop NFTs to four-repeat wild-type (4RWT) tau transgenic and nontransgenic mice that do not develop NFT pathology. Immunoprecipitation and immunoblotting experiments show that transglutaminase cross-links phosphorylated tau in the hindbrain of P301L tau transgenic mice but not in mice overexpressing 4RWT tau and nontransgenic mice. Cross-linked, phosphorylated tau from P301L tau transgenic mice runs as high-molecular mass aggregates on Western blots, similar to cross-linked tau from paired helical filaments of Alzheimer's disease. We also used double-label immunofluorescence to demonstrate colocalization of PHF-1-immunoreactive tau and the transglutaminase-catalyzed cross-link in the hindbrain, spinal cord, and cortex of P301L tau transgenic mice. In the spinal cord, 87% of PHF-1-labeled cells colocalize with the transglutaminase-catalyzed cross-link. Additionally, transglutaminase enzymatic activity is significantly elevated in the spinal cord of P301L tau transgenic mice. These studies further implicate transglutaminase in the formation and/or stabilization of NFT and paired helical filaments and provide a model system to investigate the therapeutic potential of transglutaminase inhibitors in tauopathies.
authors.affiliation: Department of Pharmacology, Loyola University Chicago Medical Center, Maywood, Illinois 60153, USA.
authors.forename: Robyn A
authors.initials: RA
authors.lastname: Halverson
authors.forename: Jada
authors.initials: J
authors.lastname: Lewis
authors.forename: Shanti
authors.initials: S
authors.lastname: Frausto
authors.forename: Mike
authors.initials: M
authors.lastname: Hutton
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Muma
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001923:Brain Chemistry; D004198:Disease Susceptibility; D051379:Mice; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D008970:Molecular Weight; D009069:Movement Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D009410:Nerve Degeneration; D016874:Neurofibrillary Tangles / Q000378:metabolism*; D017354:Point Mutation; D013116:Spinal Cord / Q000737:chemistry; D013329:Structure-Activity Relationship; D011503:Transglutaminases / Q000378:metabolism*; D016875:tau Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D016875:tau Proteins; D011503:Transglutaminases