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Cited by 47Amyotrophic Lateral Sclerosis ResearchRNA Research and SplicingRNA Interference and Gene Delivery

TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity

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Romano, Giulia, Klima, Raffaella, Feiguin, Fabian·2020·BMC Biology
DOI 10.1186/s12915-020-00816-1PMC PMC7334854
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Abstract

BACKGROUND: Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is also characterized by aberrant expression of retrotransposable elements (RTEs). Although the TDP-43 function was shown to be required in the neurons and glia to maintain the organization of neuromuscular synapses and prevent denervation of the skeletal muscles, the molecular mechanisms involved in physiological dysregulation remain elusive. Here, we address this issue using a null mutation of the TDP-43 Drosophila homolog, TBPH. RESULTS: Using genome-wide gene expression profiles, we detected a strong upregulation of RTE expression in TBPH-null Drosophila heads, while the genetic rescue of the TDP-43 function reverted these modifications. Furthermore, we found that TBPH modulates the small interfering RNA (siRNA) silencing machinery responsible for RTE repression. Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposon activation and promote motoneuron axonal wrapping and synaptic growth in TBPH-null Drosophila. CONCLUSIONS: We identified an upregulation of RTE expression in TBPH-null Drosophila heads and demonstrate that defects in the siRNA pathway lead to RTE upregulation and motoneuron degeneration. Our results describe a novel physiological role of endogenous TDP-43 in the prevention of RTE-induced neurological alterations through the modulation of Dicer-2 activity and the siRNA pathway.

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  • Genetic perturbations to TDP-43 consistently cause increased expression of retrotransposons.

    “Genetic perturbations to TDP-43 consistently cause increased expression of retrotransposons.”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Romano et al. 2020

    The Results section (‘The lack of TBPH induces the expression of retrotransposons in Drosophila’; page unavailable) reports increased accord and gypsy expression in two null alleles of the fly TDP-43 homolog, with genetic rescue reversing their activation. The Discussion also describes retrotransposon activation in a fly model overexpressing human TDP-43. These findings support an association for the perturbations described, but not the unqualified assertion that genetic perturbations to TDP-43 consistently increase retrotransposon expression. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Knockout of TBPH, the Drosophila ortholog of TDP-43, triggers retrotransposon expression during larval development.

    “the Feiguin group (Romano et al. 2020) demonstrated that knockout of TBPH, the Drosophila ortholog of TDP-43, triggers retrotransposon expression during larval development”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Romano et al. 2020

    The Results section, “The lack of TBPH induces the expression of retrotransposons in Drosophila” (page unavailable), reports increased accord and gypsy expression in TBPH-null flies, establishing the core claim. But that expression analysis used adult heads. The paper also examines TBPH-null larvae, without clearly establishing in our copy that the reported increase in retrotransposon expression occurred during larval development. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • NRTIs reduce the toxicity of transgenic TDP-43 overexpression or knockout of the endogenous fly ortholog.

    “Similarly, NRTIs reduce the toxicity of transgenic TDP-43 overexpression (Krug et al. 2017) or knockout of the endogenous fly ortholog (Romano et al. 2020).”

    From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Romano et al. 2020

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Cited by

Sorted by citations

Authors
Romano, G., Klima, R., & Feiguin, F.
Affiliations
International Centre for Genetic Engineering and Biotechnology (IT)
Corresponding author
Feiguin, Fabian
ORCID
Venue
BMC Biology
Publisher
Springer Science and Business Media LLC
Published
2020-07-03
Volume
18
Issue
1
Pages
82-82
ISSN
1741-7007 (ISSN-L)
DOI
10.1186/s12915-020-00816-1
PMC
PMC7334854
OpenAlex
W3040529067
Cited by
47
References
4
Citations by year
2026: 7 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 6 · 2021: 6 · 2020: 2
FWCI
2.27
Type
journal article
Language
en
Open access
Licence
Locations
  • BMC Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion, public-domain)
  • ArTS Archivio della ricerca di Trieste (University of Trieste https://www.units.it/) (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
Funders
  • AriSLA
  • BENEFICENTIA Stiftung.
Topics
  • Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
Keywords
TDP-43, TBPH, retrotransposons, Dicer-2, siRNA pathway, amyotrophic lateral sclerosis, motor system, motor neuron degeneration, synaptic growth, small RNA silencing, Drosophila
MeSH terms
Animals, DNA-Binding Proteins, Drosophila melanogaster, Motor Neurons, Retroelements, Endogenous Retroviruses, RNA Helicases, Drosophila Proteins, Ribonuclease III, Transcriptome

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