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Elevated nuclear TDP-43 induces constitutive exon skipping
Open accessPreprint — published as 10.1186/s13024-024-00732-w · Paper page
Abstract
Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Our findings emphasize the need for caution in interpreting TDP-43 overexpression data, and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy. Understanding the subtle aspects of TDP-43 toxicity within different subcellular locations is essential for the development of therapies targeting neurodegenerative disease.
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Metadata
- Authors
- Carmen-Orozco, R. P., Tsao, W., Ye, Y., Sinha, I. R., Chang, K., Trinh, V., Chung, W., Bowden, K., Troncoso, J. C., Blackshaw, S., Hayes, L. R., Sun, S., Wong, P. C., & Ling, J. P.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Ling, Jonathan P.
- ORCID
- Venue
- Molecular Neurodegeneration
- Publisher
- openRxiv
- Published
- 2023-05-12
- Volume
- 19
- Issue
- 1
- Pages
- 45-45
- ISSN
- 1750-1326 (ISSN-L)
- PMC
- PMC11163724
- OpenAlex
- W4399470354
- Cited by
- 27
- References
- 1
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 6
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Molecular Neurodegeneration (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Science Foundation (1920103, 2139757)
- Johns Hopkins University
- National Institutes of Health (1rf1mh123237-01, 1r21ag072078-01, 1rf1ns113820-01)
- National Institute on Aging (U19AG033655, P30AG066507)
- National Institute of Neurological Disorders and Stroke (R01NS107347, R01NS095969, R01NS123538)
- Topics
- Health Sciences › Medicine › Clinical Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- TDP-43, gain-of-function, cryptic exons, neurodegenerative disease models, RNA splicing, TDP-43 proteinopathy
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