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ORIGINAL RESEARCH article

Front. Cell Dev. Biol.

Sec. Molecular and Cellular Pathology

Volume 13 - 2025 | doi: 10.3389/fcell.2025.1677090

This article is part of the Research TopicDrosophila Models of Human Development and DiseaseView all articles

TDP-43-mediated Amyotrophic Lateral Sclerosis: new/hidden insights from Drosophila

Provisionally accepted
  • 1Department of Biology, University of Padua, Padua, Italy
  • 2Department of Pharmaceutical Sciences, Universita degli Studi di Perugia, Perugia, Italy
  • 3Department of Life and Environmental Sciences, Universita degli Studi di Cagliari, Cagliari, Italy

The final, formatted version of the article will be published soon.

Transactive response DNA-binding protein 43 (TDP-43) is a key factor in motor neurons and related neurodegenerative disorders, and the presence of cytoplasmic aggregates of TDP-43 is a major hallmark of diseases such amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Nevertheless, little is known about early developmental effects or the systemic nature of TDP-43-mediated pathology. Drosophila melanogaster is acknowledged as a powerful genetic model for studying the genetic inheritance and the behavioral and developmental processes associated with human neurodegenerative diseases, including ALS. To better understand the possible roles and potential pathogenic mechanisms of TDP-43 protein in the pathogenesis of ALS, we performed a transcriptomic analysis of larvae from a Drosophila model knock-out (KO) for the TBPH gene, the fly TDP-43 ortholog. Interestingly, the Gene Ontology (GO) analysis highlighted some pathways not yet associated with this pathology and this model. We identified several genes encoding for serine proteases, a class of enzymes that in the central nervous system (CNS) play important roles in neural development, synaptic plasticity, and neurodegeneration. Our work provides insights into novel pathological mechanisms underlying the disease, thereby opening new pathways for drug discovery.

Keywords: TDP-43, Amyotrophic Lateral Sclerosis, Drosophila melanogaster, TBPH, Gene Expression

Received: 31 Jul 2025; Accepted: 06 Oct 2025.

Copyright: © 2025 Colaianni, Ceccato, Antolini, Conte, De Pitta, Feiguin and Mazzotta. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Gabriella M Mazzotta, gabriella.mazzotta@unipd.it

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