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 pens 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 pens 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 tan in straight and PHFs leading to neurofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.