Cited by 205Alzheimer's disease research and treatmentsRNA Research and SplicingAmyotrophic Lateral Sclerosis Research

Tau-mediated disruption of the spliceosome triggers cryptic rna splicing and neurodegeneration in Alzheimer's Disease

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Hsieh, Yi-Chen, Guo, Caiwei, Yalamanchili, Hari K., Abreha, Measho, Al-Ouran, Rami, Li, Yarong, Dammer, Eric B., Lah, James J. +6 more·2019·Cell Reports

Published version of a preprint

Abstract

In Alzheimer's disease (AD), spliceosomal proteins with critical roles in RNA processing aberrantly aggregate and mislocalize to Tau neurofibrillary tangles. We test the hypothesis that Tau-spliceosome interactions disrupt pre-mRNA splicing in AD. In human postmortem brain with AD pathology, Tau coimmunoprecipitates with spliceosomal components. In Drosophila, pan-neuronal Tau expression triggers reductions in multiple core and U1-specific spliceosomal proteins, and genetic disruption of these factors, including SmB, U1-70K, and U1A, enhances Tau-mediated neurodegeneration. We further show that loss of function in SmB, encoding a core spliceosomal protein, causes decreased survival, progressive locomotor impairment, and neuronal loss, independent of Tau toxicity. Lastly, RNA sequencing reveals a similar profile of mRNA splicing errors in SmB mutant and Tau transgenic flies, including intron retention and non-annotated cryptic splice junctions. In human brains, we confirm cryptic splicing errors in association with neurofibrillary tangle burden. Our results implicate spliceosome disruption and the resulting transcriptome perturbation in Tau-mediated neurodegeneration in AD.

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Crossref · 10.1016/j.celrep.2019.08.104

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  • Small quantities of MAP2 have been identified in neurofibrillary tangles.

    “Nevertheless, small quantities of MAP2 have been identified in neurofibrillary tangles (34, 35), and interactome studies in human AD brain have captured MAP2 together with oligomeric tau (35, 36).”

    From MAP2 caps tau fibrils and inhibits aggregation (2023) · cites this paper as [36]

    The Introduction says tau forms neurofibrillary tangles, and the Results discuss spliceosome components associated with tangles, but neither identifies MAP2 in them. Searches for MAP2 and microtubule-associated protein 2 found no passage in our copy addressing MAP2’s presence or quantity in tangles; page numbers were unavailable. (LLM, conf=0.75)

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2 of the 122 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Hales CM, Dammer EB, Diner I, Yi H, Seyfried NT, Gearing M, Glass JD, Montine TJ, Levey AI, and Lah JJ (2014). Aggregates of small nuclear ribonucleic acids (snRNAs) in Alzheimer’s disease. Brain Pathol. 24, 344– 351. 24571648 PMC4096308

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Authors
Hsieh, Y.-C., Guo, C., Yalamanchili, H. K., Abreha, M., Al-Ouran, R., Li, Y., Dammer, E. B., Lah, J. J., Levey, A. I., Bennett, D. A., De Jager, P. L., Seyfried, N. T., Liu, Z., & Shulman, J. M.
Affiliations
  • Baylor College of Medicine (US)
  • Emory University (US)
  • Rush University Medical Center (US)
Corresponding author
Shulman, Joshua M.
Venue
Cell Reports
Publisher
Elsevier BV
Published
2019-10
Volume
29
Issue
2
Pages
301-316.e10
ISSN
2211-1247 (ISSN-L)
OpenAlex
W2912165492
Cited by
196
References
122
Citations by year
2026: 30 · 2025: 33 · 2024: 34 · 2023: 23 · 2022: 22 · 2021: 36 · 2020: 13 · 2019: 4
FWCI
14.58
Type
journal article
Language
en
Open access
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • SSRN Electronic Journal (acceptedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Cancer Prevention and Research Institute of Texas (RP170387)
  • Texas Children's Hospital
  • National Institutes of Health (P30CA125123, R01AG15819, R01AG053960, U01AG046161, R01GM120033, U01AG46152, R01AG050631, U01AG061357, U54HD083092, P30AG10161, R01AG036836, R01AG057339, R01AG17917)
  • Huffington Foundation
  • Burroughs Wellcome Fund
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
Keywords
Alzheimer's disease, tau protein, spliceosome, cryptic splicing, pre-mRNA splicing, neurodegeneration, neurofibrillary tangles, SMB, U1-70K, U1A, intron retention, Drosophila model, neuronal loss
MeSH terms
Alzheimer Disease, Animals, Brain, Drosophila, Humans, Models, Biological, Motor Activity, Nerve Degeneration, RNA Splicing, tau Proteins, Spliceosomes, Ribonucleoproteins, Small Nuclear, Drosophila Proteins

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