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bioRxiv · 10.1101/2021.02.04.429704

New lessons on TDP-43 from the killifish N. furzeri

Louka, A.·Bagnoli, S.·Rupert, J.·Esapa, B.·Tartaglia, G. G.·Cellerino, A.·Pastore, A.·Terzibasi Tozzini, E.
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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 unique advantage as a model system that it is an organism with compressed lifespan and a conserved ageing phenotype that develops within months, making this organism the available shortest-lived vertebrate with a clear ageing phenotype. Here, we show that the two paralogs of TDP-43 from the killifish N. furzeri share high sequence homology with the human protein and recapitulate its cellular and biophysical behaviour. We prove that, during ageing, N. furzeri TDP-43 spontaneously forms insoluble intracellular TDP-43 aggregates that have amyloid characteristics and colocalize with the stress granule core protein G3BP. Our results propose this organism as a valuable model of TDP-43-related pathologies and show that even minute differences between the human and N. furzeri proteins may help to shed new light onto the role of TDP-43 in RNA recognition and granule formation.

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Louka, A., Bagnoli, S., Rupert, J., Esapa, B., Tartaglia, G. G., Cellerino, A., Pastore, A., Terzibasi Tozzini, E.. 2021-02-05. New lessons on TDP-43 from the killifish N. furzeri. https://doi.org/10.1101/2021.02.04.429704

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