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Cited by 27Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingGenetic Neurodegenerative Diseases

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Elevated nuclear TDP-43 induces constitutive exon skipping

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Carmen-Orozco, Rogger P., Tsao, William, Ye, Yingzhi, Sinha, Irika R., Chang, Koping, Trinh, Vickie T., Chung, William, Bowden, Kyra, Troncoso, Juan C., Blackshaw, Seth, Hayes, Lindsey R., Sun, Shuying, Wong, Philip C., Ling, Jonathan P.·2024·Molecular Neurodegeneration
DOI 10.1186/s13024-024-00732-wPMC PMC11163724

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Abstract

Background: 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. Methods: We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. Results: 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. Conclusions: 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.

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Metadata

Authors
Carmen-Orozco, R. P., Tsao, W., Ye, Y., Sinha, I. R., Chang, K., Trinh, V. T., 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
Springer Science and Business Media LLC
Published
2024-06-09
Volume
19
Issue
1
Pages
45-45
ISSN
1750-1326 (ISSN-L)
DOI
10.1186/s13024-024-00732-w
PMC
PMC11163724
OpenAlex
W4399470354
Cited by
27
References
10
Citations by year
2026: 6 · 2025: 15 · 2024: 6
FWCI
7.19
Type
journal article
Language
en
Open access
Licence
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
NIH (RF1MH123237, P30AG066507, U19AG033655, R01NS123538, R01NS107347, RF1NS113820, R21AG072078, R01NS095969)
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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