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Direct analysis of tau from PSP brain identifies new phosphorylation sites and a major fragment of N‐terminally cleaved tau containing four microtubule‐binding repeats
Author(s) -
Wray Selina,
Saxton Malcolm,
Anderton Brian H.,
Hanger Diane P.
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05321.x
Subject(s) - progressive supranuclear palsy , corticobasal degeneration , tauopathy , tau protein , phosphorylation , frontotemporal lobar degeneration , chemistry , alzheimer's disease , microbiology and biotechnology , biochemistry , frontotemporal dementia , biology , dementia , neurodegeneration , genetics , disease , pathology , medicine , atrophy
Tangles containing hyperphosphorylated aggregates of insoluble tau are a pathological hallmark of progressive supranuclear palsy (PSP). Several phosphorylation sites on tau in PSP have been identified using phospho‐specific antibodies, but no sites have been determined by direct sequencing due to the difficulty in enriching insoluble tau from PSP brain. We describe a new method to enrich insoluble PSP‐tau and report eight phosphorylation sites [Ser46, Thr181, Ser202, Thr217, Thr231, Ser235, Ser396/Ser400 (one site) and Thr403/Ser404 (one site)] identified by mass spectrometry. We also describe a 35 kDa C‐terminal tau fragment (tau35), lacking the N‐terminus of tau but containing four microtubule‐binding repeats (4R), that is present only in neurodegenerative disorders in which 4R tau is over‐represented. Tau35 was readily detectable in PSP, corticobasal degeneration and 4R forms of fronto‐temporal dementia with parkinsonism linked to chromosome 17, but was absent from control, Alzheimer’s disease and Pick’s disease brain. Our findings suggest the aggregatory characteristics of PSP‐tau differ from those of insoluble tau in Alzheimer’s disease brain and this might be related to the presence of a C‐terminal cleavage product of tau.