Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy.
The mechanisms leading to the abnormal self-polymerization of tau into straight and paired helical filaments (PHFs) and neurofibrillary tangles (NFT) in Alzheimer disease (AD) and progressive supranuclear palsy (PSP) are not known. However, transglutaminase-induced cross-linking of PHF-tau was observed in AD and thus may also contribute to the formation of NFT in other neurodegenerative disorders including PSP. Tissue homogenates from PSP and normal age-matched controls were used to immunoaffinity-purify proteins containing transglutaminase-induced epsilon-(gamma-glutamyl) lysine cross-links. The immunoaffinity-purified proteins were then examined on immunoblots with a PHF-tau antibody, PHF-1. There were significantly higher levels of epsilon-(gamma-glutamyl) lysine cross-linking of PHF-tau in globus pallidus and pons regions of PSP cases compared to barely detectable cross-links in controls. The occipital cortex, an area spared from neurofibrillary pathology in PSP, showed no detectable cross-linking of PHF-tau protein in either PSP cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pons of PSP Previous studies and present data are consistent with the hypothesis that transglutaminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tau in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.
Zemaitaitis
M O
MO
Department of Pharmacology, Loyola University Chicago Medical Center, Maywood, Illinois 60153, USA.
Lee
J M
JM
Troncoso
J C
JC
Muma
N A
NA
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D003432:Cross-Linking Reagents; D005917:Globus Pallidus / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009778:Occipital Lobe / Q000378:metabolism*; D011149:Pons / Q000378:metabolism* / Q000473:pathology; D013494:Supranuclear Palsy, Progressive / Q000378:metabolism* / Q000473:pathology; D011503:Transglutaminases / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D003432:Cross-Linking Reagents; D016875:tau Proteins; D011503:Transglutaminases