Tau-mediated disruption of the spliceosome triggers cryptic rna splicing and neurodegeneration in Alzheimer's Disease
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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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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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NORMA: The Network Makeup Artist — A Web Tool for Network Annotation Visualization
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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.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 29
- Issue
- 2
- Pages
- 301-316.e10
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC6919331
- 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
- gold
- doi.org
- Licence
- 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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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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