Dual modification of Alzheimer's disease PHF-tau protein by lysine methylation and ubiquitylation: A mass spectrometry approach

Greenebaum Cancer Center, University of Maryland, Baltimore, MD 21201, USA.
Acta Neuropathologica (Impact Factor: 10.76). 01/2012; 123(1):105-17. DOI: 10.1007/s00401-011-0893-0
Source: PubMed


In sporadic Alzheimer’s disease (AD), neurofibrillary lesion formation is preceded by extensive post-translational modification of the microtubule associated protein tau. To identify the modification signature associated with tau lesion formation at single amino acid resolution, immunopurified paired helical filaments were isolated from AD brain and subjected to nanoflow liquid chromatography–tandem mass spectrometry analysis. The resulting spectra identified monomethylation of lysine residues as a new tau modification. The methyl-lysine was distributed among seven residues located in the projection and microtubule binding repeat regions of tau protein, with one site, K254, being a substrate for a competing lysine modification, ubiquitylation. To characterize methyl lysine content in intact tissue, hippocampal sections prepared from post mortem late-stage AD cases were subjected to double-label confocal fluorescence microscopy using anti-tau and anti-methyl lysine antibodies. Anti-methyl lysine immunoreactivity colocalized with 78 ± 13% of neurofibrillary tangles in these specimens. Together these data provide the first evidence that tau in neurofibrillary lesions is post-translationally modified by lysine methylation.

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    • "The highly phosphorylated ordered structures comprised of insoluble tau that are observed in human tauopathies are in stark contrast to normal tau protein that exists in a moderately phosphorylated soluble form and is predominantly found in neurons. Post-translational modifications of tau are common features in tauopathy, and include changes in serine/threonine and tyrosine phosphorylation [9] [10] [11], ubiquitination [12], acetylation [13], methylation [14], nitration [15], and truncation [16]. However, although a number of protein kinases have been suggested as candidates for tau modification in the tauopathies, the identity of the critical kinases that might trigger tau pathogenesis, remain enigmatic [17]. "
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    • "In addition to the influence that PTMs exert on tau function individually, it is thought that various modifications may cooperate and compete in a coordinated fashion. For example, recently two modifications have been identified that are also lysine directed: acetylation [120] [121] and methylation [117]. Because these modifications both directly compete with ubiquitin for lysine site occupancy, there is potential for acetylation and methylation to directly affect the rate of turnover of tau protein and its motility through the endocytic pathway. "
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