Cited by 124Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchAdvanced Proteomics Techniques and Applications

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

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Thomas, Stefani N., Funk, Kristen E., Wan, Yunhu, Liao, Zhongping, Davies, Peter, Kuret, Jeff, Yang, Austin J.·2012·Acta Neuropathologica

Abstract

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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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.
Venue
Acta Neuropathologica
Published
2011-10-28
Volume
123
Issue
1
Pages
105-117
ISSN
  • 0001-6322 (ISSN-L)
  • 1432-0533
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
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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