Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model.

Overview

1. Program in Neuroscience, Department of Neurobiology and Behavior, Stony Brook University, New York, United States of America
2. Department of Anesthesiology, Stony Brook School of Medicine, New York, United States of America

Abstract

The most common genetic cause of both familial amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is an expanded G4C2 repeat in the first intron of the gene C9orf72. The C9orf72 repeat expansion is bidirectionally transcribed into sense and anti-sense RNA foci, and also produces dipeptide repeats (DPRs) via a non-canonical translation mechanism known as repeat-associated (RAN) translation. Each of these components of the G4C2 repeat expansion cause neurodegenerative effects in animal models when expressed in neurons, but impacts from glial expression are more poorly understood. Here, we use glial cell type-specific expression of individual DPRs, of RNA repeat-only, or of the G4C2 repeat, that produces both DPRs and RNA repeats, to systematically investigate glial toxicity of each component. We find that as with neurons, the GR and G4C2 transgenes produce the highest degree of toxicity when expressed in glia. Each of these transgenes are capable to produce the GR DPR, which also is the most toxic factor in neurons. We demonstrate that both the GR and G4C2 transgenes cause activation of mdg4, an endogenous retrovirus (ERV). Such ERV expression is a hallmark of TDP-43 dysfunction that is commonly observed in C9orf72 patients. We find that glial expression of either the GR or the G4C2 transgene is toxic to glial cells, but such expression does not cause loss nearby neurons. However, blocking apoptotic signaling within glia that express either GR or G4C2 via expression of the p35 caspase inhibitor further exacerbates effects on lifespan and ablating such glia via expression of the proapoptotic reaper gene partially ameliorates these effects. Together, these results indicate that expression of toxic C9orf72 components in glia produces deleterious effects on lifespan, though potentially through different mechanisms than seen in TDP-43 models of ALS/FTD.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Data

Datasets cited

• doi:10.5061/dryad.1ns1rn98g, at Dryad; found in DataCite

Data Availability

All numerical/quantitative data are supplied as part of the manuscript and supplemental files. Raw image stacks from each confocal microscopy sample have been uploaded to Dryad and a reviewer link is provided.Permanent link to raw image stacks is contained within the manuscript.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 2 authors, 11 MeSH terms, 1 funder, 59 references.

Cite

This paper

Hubbard, I., & Dubnau, J. (2026). Glial cell toxicity in a Drosophila C9orf72 neurodegeneration model. PLoS genetics, 22(8), e1011909. https://doi.org/10.1371/journal.pgen.1011909

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