期刊
JOURNAL OF NEUROCHEMISTRY
卷 105, 期 6, 页码 2343-2352出版社
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2008.05321.x
关键词
Alzheimer's disease; cleavage; phosphorylation; progressive supranuclear palsy; tau
资金
- Medical Research Council [G0400050] Funding Source: Medline
- Alzheimers Research UK [ART-EG2004A-1] Funding Source: researchfish
- MRC [G0400050] Funding Source: UKRI
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.
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