TDP-43-mediated amyotrophic lateral sclerosis: new/hidden insights from Drosophila

TL;DR

This study uses fruit flies to uncover new pathways linked to TDP-43-related diseases like ALS, highlighting serine proteases as potential targets for treatment.

Contribution

The study reveals novel pathways involving serine proteases in TDP-43-mediated ALS using a Drosophila model.

Findings

Transcriptomic analysis of Drosophila larvae lacking TBPH (TDP-43 ortholog) identified serine protease-related pathways.

These pathways are linked to neural development and neurodegeneration but had not been previously associated with TDP-43 pathology.

The findings suggest new potential therapeutic targets for ALS and related diseases.

Abstract

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.

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