New lessons on TDP-43 from old N. furzeri killifish: A new animal model of TDP-43-associated neurodegeneration

Alexandra Louka; Sara Bagnoli; Jakob Rupert; Benjamin  Esapa; Gian Gaetano Tartaglia; Alessandro  Cellerino; Annalisa Pastore; Eva  Terzibasi Tozzini

doi:10.1111/acel.13517

New lessons on TDP-43 from old N. furzeri killifish: A new animal model of TDP-43-associated neurodegeneration

Alexandra Louka, Sara Bagnoli, Jakob Rupert, Benjamin Esapa, Gian Gaetano Tartaglia, Alessandro Cellerino, Annalisa Pastore^*, Eva Terzibasi Tozzini^*

^*Corresponding author for this work

Basic and Clinical Neuroscience

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurable
neurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. This
is an essential DNA/RNA binding protein involved in transcription regulation, pre-RNA
processing and RNA transport. Having suitable animal models to study the mechanisms of
TDP-43 aggregation is crucial to develop treatments against disease. We have previously
demonstrated that the killifish Nothobranchius furzeri offers the advantage of being the
shortest-lived vertebrate with a clear aging phenotype.
Here, we show that the two N. furzeri paralogs of TDP-43 share high sequence homology with
the human protein and recapitulate its cellular and biophysical behavior. During aging, N.
furzeri TDP-43 spontaneously forms insoluble intracellular aggregates with amyloid
characteristics and colocalizes with stress granules. Our results propose this organism as a
valuable new model of TDP-43-related pathologies making it a powerful tool for the study of
disease mechanism.

Original language	English
Journal	AGING CELL
DOIs	https://doi.org/10.1111/acel.13517
Publication status	Published - 22 Dec 2021

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title = "New lessons on TDP-43 from old N. furzeri killifish: A new animal model of TDP-43-associated neurodegeneration",

abstract = "Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurableneurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. Thisis an essential DNA/RNA binding protein involved in transcription regulation, pre-RNAprocessing and RNA transport. Having suitable animal models to study the mechanisms ofTDP-43 aggregation is crucial to develop treatments against disease. We have previouslydemonstrated that the killifish Nothobranchius furzeri offers the advantage of being theshortest-lived vertebrate with a clear aging phenotype.Here, we show that the two N. furzeri paralogs of TDP-43 share high sequence homology withthe human protein and recapitulate its cellular and biophysical behavior. During aging, N.furzeri TDP-43 spontaneously forms insoluble intracellular aggregates with amyloidcharacteristics and colocalizes with stress granules. Our results propose this organism as avaluable new model of TDP-43-related pathologies making it a powerful tool for the study ofdisease mechanism.",

author = "Alexandra Louka and Sara Bagnoli and Jakob Rupert and Benjamin Esapa and Tartaglia, {Gian Gaetano} and Alessandro Cellerino and Annalisa Pastore and {Terzibasi Tozzini}, Eva",

note = "Funding Information: This work was supported by the Dementia Research UK (RE1 3556). GGT's research was supported by European Research Council (RIBOMYLOME_309545 and ASTRA_855923), the H2020 projects IASIS_727658 and INFORE_825080, the Spanish Ministry of Economy and Competitiveness BFU2017‐86970‐P, the European Union's Horizon 2020 research, and innovation programme under the Marie Sk{\l}odowska‐Curie grant agreement No 754490 within the MINDED project Publisher Copyright: {\textcopyright} 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.",

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AU - Louka, Alexandra

AU - Bagnoli, Sara

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AU - Esapa, Benjamin

AU - Tartaglia, Gian Gaetano

AU - Cellerino, Alessandro

AU - Pastore, Annalisa

AU - Terzibasi Tozzini, Eva

N1 - Funding Information: This work was supported by the Dementia Research UK (RE1 3556). GGT's research was supported by European Research Council (RIBOMYLOME_309545 and ASTRA_855923), the H2020 projects IASIS_727658 and INFORE_825080, the Spanish Ministry of Economy and Competitiveness BFU2017‐86970‐P, the European Union's Horizon 2020 research, and innovation programme under the Marie Skłodowska‐Curie grant agreement No 754490 within the MINDED project Publisher Copyright: © 2021 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.

PY - 2021/12/22

Y1 - 2021/12/22

N2 - Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurableneurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. Thisis an essential DNA/RNA binding protein involved in transcription regulation, pre-RNAprocessing and RNA transport. Having suitable animal models to study the mechanisms ofTDP-43 aggregation is crucial to develop treatments against disease. We have previouslydemonstrated that the killifish Nothobranchius furzeri offers the advantage of being theshortest-lived vertebrate with a clear aging phenotype.Here, we show that the two N. furzeri paralogs of TDP-43 share high sequence homology withthe human protein and recapitulate its cellular and biophysical behavior. During aging, N.furzeri TDP-43 spontaneously forms insoluble intracellular aggregates with amyloidcharacteristics and colocalizes with stress granules. Our results propose this organism as avaluable new model of TDP-43-related pathologies making it a powerful tool for the study ofdisease mechanism.

AB - Frontotemporal dementia and amyotrophic lateral sclerosis are fatal and incurableneurodegenerative diseases linked to the pathological aggregation of the TDP-43 protein. Thisis an essential DNA/RNA binding protein involved in transcription regulation, pre-RNAprocessing and RNA transport. Having suitable animal models to study the mechanisms ofTDP-43 aggregation is crucial to develop treatments against disease. We have previouslydemonstrated that the killifish Nothobranchius furzeri offers the advantage of being theshortest-lived vertebrate with a clear aging phenotype.Here, we show that the two N. furzeri paralogs of TDP-43 share high sequence homology withthe human protein and recapitulate its cellular and biophysical behavior. During aging, N.furzeri TDP-43 spontaneously forms insoluble intracellular aggregates with amyloidcharacteristics and colocalizes with stress granules. Our results propose this organism as avaluable new model of TDP-43-related pathologies making it a powerful tool for the study ofdisease mechanism.

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New lessons on TDP-43 from old N. furzeri killifish: A new animal model of TDP-43-associated neurodegeneration

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