Transglutaminase-induced cross-linking of tau proteins in progressive supranuclear palsy

The mechanisms leading to the abnormal self-polymerization of tau into stra ight 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 obser ved in AD and thus may also contribute to the formation of NFT in other neu rodegenerative disorders including PSP. Tissue homogenates from PSP and nor mal age-matched controls were used to immunoaffinity-purify proteins contai ning transglutaminase-induced epsilon-(gamma -glutamyl) lysine cross-links. The immunoaffinity-purified proteins were then examined on immunoblots wit h a PHF-tau antibody, PHF-1. There were significantly higher levels of epsi lon-(gamma -glutamyl) lysine cross-linking of PHF-tau in globus pallidus an d pens regions of PSP cases compared to barely detectable cross-links in co ntrols. The occipital cortex, an area spared from neurofibrillary pathology in PSP; showed no detectable cross-linking of PHF-tau protein in either PS P cases or control cases. Double-label immunofluorescence demonstrated the colocalization of the cross-link and PHF-tau in NFT in pens of PSP. Previou s studies and present data are consistent with the hypothesis that transglu taminase-induced cross-linking may be a factor contributing to the abnormal polymerization and stabilization of tan in straight and PHFs leading to ne urofibrillary tangle formation in neurodegenerative diseases, including PSP and AD.