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26-07-2023 | Fingolimod | Original Article

A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy

Authors: Luca Lo Piccolo, Takanari Umegawachi, Ranchana Yeewa, Saranyapin Potikanond, Wutigri Nimlamool, Virapong Prachayasittikul, Yusuke Gotoh, Hideki Yoshida, Masamitsu Yamaguchi, Salinee Jantrapirom

Published in: Neurotherapeutics | Issue 5/2023

Abstract

Pathogenic changes to TAR DNA-binding protein 43 (TDP-43) leading to alteration of its homeostasis are a common feature shared by several progressive neurodegenerative diseases for which there is no effective therapy. Here, we developed Drosophila lines expressing either wild type TDP-43 (WT) or that carrying an Amyotrophic Lateral Sclerosis /Frontotemporal Lobar Degeneration-associating G384C mutation that recapitulate several aspects of the TDP-43 pathology. To identify potential therapeutics for TDP-43-related diseases, we implemented a drug repurposing strategy that involved three consecutive steps. Firstly, we evaluated the improvement of eclosion rate, followed by the assessment of locomotive functions at early and late developmental stages. Through this approach, we successfully identified fingolimod, as a promising candidate for modulating TDP-43 toxicity. Fingolimod exhibited several beneficial effects in both WT and mutant models of TDP-43 pathology, including post-transcriptional reduction of TDP-43 levels, rescue of pupal lethality, and improvement of locomotor dysfunctions. These findings provide compelling evidence for the therapeutic potential of fingolimod in addressing TDP-43 pathology, thereby strengthening the rationale for further investigation and consideration of clinical trials. Furthermore, our study demonstrates the utility of our Drosophila-based screening pipeline in identifying novel therapeutics for TDP-43-related diseases. These findings encourage further scale-up screening endeavors using this platform to discover additional compounds with therapeutic potential for TDP-43 pathology.

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Title: A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy
Authors: Luca Lo Piccolo
Takanari Umegawachi
Ranchana Yeewa
Saranyapin Potikanond
Wutigri Nimlamool
Virapong Prachayasittikul
Yusuke Gotoh
Hideki Yoshida
Masamitsu Yamaguchi
Salinee Jantrapirom
Publication date: 26-07-2023
Publisher: Springer International Publishing
Keywords: Fingolimod
Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Frontotemporal Dementia
Published in: Neurotherapeutics / Issue 5/2023
Print ISSN: 1933-7213
Electronic ISSN: 1878-7479
DOI: https://doi.org/10.1007/s13311-023-01406-z

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ERS Congress 2024

Springer Medicine

A Novel Drosophila-based Drug Repurposing Platform Identified Fingolimod As a Potential Therapeutic for TDP-43 Proteinopathy

Abstract

Advances in Alzheimer's

ERS Congress 2024

Springer Medicine

Abstract

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Advances in Alzheimer's