Dual modification of Alzheimer’s disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach
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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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Lys residues are predominately monomethylated in aging or AD cohorts.
“a recent study suggests that Lys residues are predominately monomethylated in aging or AD cohorts [174–176].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [175]
Methylated Lys residues mainly distribute to the projection region and tau microtubule-binding domain.
“Methylated Lys residues mainly distribute to the projection region and tau microtubule-binding domain [174–176].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [175]
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- Authors
- Thomas, S. N., Funk, K. E., Wan, Y., Liao, Z., Davies, P., Kuret, J., & Yang, A. J.
- Affiliations
- University of Maryland, Baltimore (US)
- The Ohio State University (US)
- Albert Einstein College of Medicine (US)
- Corresponding author
- Kuret, Jeff
- Yang, Austin J.
- ORCID
- Venue
- Acta Neuropathologica
- Published
- 2011-10-28
- Volume
- 123
- Issue
- 1
- Pages
- 105-117
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC3249157
- OpenAlex
- W2155022431
- Cited by
- 123
- References
- 67
- Citations by year
- 2026: 7 · 2025: 12 · 2024: 14 · 2023: 8 · 2022: 10 · 2021: 14 · 2020: 7 · 2019: 9 · 2018: 9 · 2017: 14 · 2016: 5 · 2015: 3 · 2014: 7 · 2013: 1 · 2012: 3
- FWCI
- 2.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Acta Neuropathologica (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Funders
- Ohio State University (P30-NS045758)
- University of Rochester
- National Institutes of Health (NS045758)
- National Institute on Aging (AG 25323, R01AG014452, AG 14452, R01AG025323)
- National Institute of Mental Health (MH 59786, R01MH059786)
- National Institute of Neurological Disorders and Stroke (P30NS045758)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Physical Sciences › Chemistry › Spectroscopy › Advanced Proteomics Techniques and Applications
- Keywords
- Alzheimer's disease, tau protein, lysine methylation, ubiquitination, post-translational modification, paired helical filaments, neurofibrillary tangles, microtubule-binding repeats, hippocampus
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amino Acid Sequence, Female, Humans, Lysine, Male, Methylation, Middle Aged, Molecular Sequence Data, Phosphorylation, Protein Processing, Post-Translational, Neurofibrillary Tangles, tau Proteins, Tandem Mass Spectrometry, Ubiquitination
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