IDENTIFICATION OF PHOSPHORYLATION SITES IN PHF-TAU FROM PATIENTS WITHGUAM AMYOTROPHIC-LATERAL-SCLEROSIS PARKINSONISM-DEMENTIA COMPLEX

Guam Amyotrophic Lateral Sclerosis/Parkinsonism-Dementia Complex (Guam ALS/PDC) is a progressive neurodegenerative disorder characterized by abundant neurofibrillary tangles (NFTs) composed of aggregated paired helical filaments (PHFs). These abnormal filaments resemble the PHFs in neurofibrillary lesions of classic Alzheimer's disease (AD), and re cent studies demonstrated that tau in Guam ALS/PDC is aberrantly phosp horylated and biochemically similar to the abnormal tau proteins (PHFt au) in classic AD. However, unlike PHFtau in AD, there is little infor mation on the specific sites of phosphorylation in PHFtau from Guam AL S/PDC. Thus, to address this important issue, we examined tangle-rich Guam ALS/PDC and AD brains by Western blot, immunoelectron microscopy and immunohistochemistry using 13 antibodies to defined phosphate-depe ndent or -independent epitopes distributed throughout AD PHFtau. These studies identified 7 previously unknown sites of phosphorylation in P HFtau from Guam ALS/PDC (i.e. Thr181, Thr231, Ser262, Ser396, Ser404, Ser422, and the site defined by monoclonal antibody AT10), all of whic h also are found in AD PHFtau. Indeed, the Western blot, light and imm unoelectron microscopic data suggest that NFTs, PHFs and PHFtau in Gua m ALS/PDC are very similar to their counterparts in classic AD. Thus, insights into mechanisms leading to the accumulation of neurofibrillar y lesions in Guam ALS/PDC may advance understanding of the pathogenesi s and biological consequences of these lesions in classic AD.