Cited by 68Alzheimer's disease research and treatmentsUbiquitin and proteasome pathwaysDementia and Cognitive Impairment Research

Lysine 63-linked ubiquitination of tau oligomers contributes to the pathogenesis of Alzheimer’s disease

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Puangmalai, Nicha, Sengupta, Urmi, Bhatt, Nemil, Gaikwad, Sagar, Montalbano, Mauro, Bhuyan, Arijit, Garcia, Stephanie, McAllen, Salome +4 more·2022·Journal of Biological Chemistry

Abstract

Ubiquitin-modified tau aggregates are abundantly found in human brains diagnosed with Alzheimer's disease (AD) and other tauopathies. Soluble tau oligomers (TauO) are the most neurotoxic tau species that propagate pathology and elicit cognitive deficits, but whether ubiquitination contributes to tau formation and spreading is not fully understood. Here, we observed that K63-linked, but not K48-linked, ubiquitinated TauO accumulated at higher levels in AD brains compared with age-matched controls. Using mass spectrometry analyses, we identified 11 ubiquitinated sites on AD brain-derived TauO (AD TauO). We found that K63-linked TauO are associated with enhanced seeding activity and propagation in human tau-expressing primary neuronal and tau biosensor cells. Additionally, exposure of tau-inducible HEK cells to AD TauO with different ubiquitin linkages (wild type, K48, and K63) resulted in enhanced formation and secretion of K63-linked TauO, which was associated with impaired proteasome and lysosome functions. Multipathway analysis also revealed the involvement of K63-linked TauO in cell survival pathways, which are impaired in AD. Collectively, our study highlights the significance of selective TauO ubiquitination, which could influence tau aggregation, accumulation, and subsequent pathological propagation. The insights gained from this study hold great promise for targeted therapeutic intervention in AD and related tauopathies.

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Authors
Puangmalai, N., Sengupta, U., Bhatt, N., Gaikwad, S., Montalbano, M., Bhuyan, A., Garcia, S., McAllen, S., Sonawane, M., Jerez, C., Zhao, Y., & Kayed, R.
Affiliations
The University of Texas Medical Branch at Galveston (US)
Corresponding author
Kayed, Rakez
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2022-04
Volume
298
Issue
4
Pages
101766
ISSN
0021-9258 (ISSN-L)
OpenAlex
W4212950915
Cited by
68
References
91
Citations by year
2026: 12 · 2025: 15 · 2024: 24 · 2023: 12 · 2022: 5
FWCI
8.67
Type
journal article
Language
en
Open access
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • American Heart Association Inc
  • NIH
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
tau oligomers, Alzheimer's disease, tauopathy, tau aggregation, seeding activity, proteasome dysfunction, lysosomal dysfunction, cell survival pathways
MeSH terms
Alzheimer Disease, Cells, Cultured, Humans, Lysine, Neurons, tau Proteins, Tauopathies, Ubiquitin, Ubiquitination

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