The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration
Open accessAbstract
A hallmark of neurodegenerative disease is focal onset of pathological protein aggregation, followed by progressive spread of pathology to connected brain regions. In amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), pathology is often associated with aggregation of TAR DNA-binding protein 43 (TDP-43). Although aggregated TDP-43 protein moves between cells, it is not clear whether and how this movement propagates the degeneration. Here, we have established a Drosophila model of human TDP-43 in which we initiated toxic expression of human TDP-43 focally within small groups of glial cells. We found that this focal onset kills adjacent neurons. Surprisingly, we show that this spreading death is caused by an endogenous retrovirus within the glia, which leads to DNA damage and death in adjacent neurons. These findings suggest a possible mechanism by which human retroviruses such as HERV-K might contribute to TDP-43-mediated propagation of neurodegeneration.
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RNA interference-mediated glial knockdown of mdg4-ERV is sufficient to ameliorate the negative effects of TDP-43 on life span, glial cell death, accumulation of DNA damage in glia and nearby neurons, and neuronal death.
“RNA interference–mediated glial knockdown of mdg4-ERV is sufficient to ameliorate the negative effects of TDP-43 on life span, glial cell death, accumulation of DNA damage in glia and nearby neurons, and neuronal death”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
The Results section, “Glial hTDP-43 Toxicity to Neurons Is Mediated by the Gypsy ERV and by DNA Damage Signaling” (page unavailable), reports that glial gypsy-IR knockdown reduced glial and neuronal cell-death markers and cell loss. The Introduction reports that blocking gypsy expression extended lifespan in an earlier study. The paper observes DNA damage in glia and nearby neurons, but the passages found do not show that gypsy knockdown reduced that damage; it calls the targeted ERV gypsy rather than establishing the name mdg4-ERV. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe individual glial cells marked by the mdg4-CLEVR reporter also exhibit DNA damage and activated caspase-3, as do nearby neurons.
“The individual glial cells marked by the mdg4-CLEVR reporter also exhibit DNA damage and activated caspase-3, as do nearby neurons”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
The Results section on glial hTDP-43 pathology (Fig. 3D–L; page unavailable) reports DNA damage and activated Caspase-3 in glia positive for the gypsy-CLEVR reporter, with both markers also observed in some nearby neurons. The claim names an mdg4-CLEVR reporter instead; our copy identifies the reporter in these experiments as gypsy-CLEVR. (LLM, conf=0.90)
Experimental — accuracy not yet measuredWork in Drosophila suggests that the mdg4-ERV is necessary to mediate the toxic impacts of pathological TDP-43.
“work in Drosophila from the Dubnau group (Chang & Dubnau 2019, 2023; Krug et al. 2017) suggests that the mdg4-ERV is necessary to mediate the toxic impacts of pathological TDP-43”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
The Results section, “Glial hTDP-43 Toxicity to Neurons Is Mediated by the Gypsy ERV and by DNA Damage Signaling” (page unavailable), reports that knocking down gypsy ERV reduced glial and neuronal cell death in the Drosophila model. This supports a mediating role, but the paper describes gypsy as contributing to toxicity; reduced cell death does not establish that it is necessary for all toxic impacts of pathological TDP-43. The cited passages call the element gypsy ERV, not mdg4-ERV. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOverexpression of human TDP-43 in glia or neurons causes hyperphosphorylated cytoplasmic TDP-43 accumulation and nuclear TDP-43 depletion.
“Overexpression of human TDP-43 in glia or neurons causes (a) hyperphosphorylated cytoplasmic TDP-43 accumulation and (b) nuclear TDP-43 depletion”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
The Introduction (page unavailable) says TDP-43 overexpression in animal models can cause cytoplasmic inclusions and loss of nuclear localization. It does not say those inclusions are hyperphosphorylated or establish both changes specifically in glia and neurons; the Results passages describe glial hTDP-43 toxicity and effects on nearby neurons instead. (LLM, conf=0.86)
Experimental — accuracy not yet measuredOverexpression of human TDP-43 in the Drosophila brain induced the derepression of retrotransposons, including the retrotransposition-competent LTR element Gypsy.
“Overexpression of human TDP-43 in the Drosophila brain induced the derepression of retrotransposons, including the retrotransposition-competent LTR element Gypsy135, 136.”
From The role of retrotransposable elements in ageing and age-associated diseases (2021) · cites this paper as [135]
Such conditions trigger non-cell-autonomous effects that cause nearby neurons to die.
“such conditions trigger non-cell-autonomous effects that cause nearby neurons to die”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
Blocking caspase-3-mediated cell death in these glia is sufficient to prevent glial loss but causes many more neurons to die.
“blocking caspase-3-mediated cell death in these glia is sufficient to prevent glial loss but causes many more neurons to die”
From The Role of Retrotransposons and Endogenous Retroviruses in Age-Dependent Neurodegenerative Disorders (2024) · cites this paper as Chang & Dubnau 2019
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References 81 · Cited by 68
- Authors
- Chang, Y.-H., & Dubnau, J.
- Affiliations
- Stony Brook School (US)
- Corresponding author
- Dubnau, Josh
- Venue
- Current Biology
- Publisher
- Elsevier BV
- Published
- 2019-10
- Volume
- 29
- Issue
- 19
- Pages
- 3135-3152.e4
- ISSN
- 0960-9822 (ISSN-L)
- PMC
- PMC6783360
- OpenAlex
- W2972083388
- Cited by
- 68
- References
- 81
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 7 · 2023: 9 · 2022: 6 · 2021: 13 · 2020: 15 · 2019: 1
- FWCI
- 5.92
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Current Biology (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging
- National Institute of Neurological Disorders and Stroke
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Keywords
- TDP-43, endogenous retroviruses, HERV-K, neurodegeneration, amyotrophic lateral sclerosis, frontotemporal dementia, Drosophila model, glial cells, DNA damage, neuronal cell death
- MeSH terms
- Animals, Disease Models, Animal, DNA-Binding Proteins, Drosophila melanogaster, Neuroglia, Neurodegenerative Diseases, Endogenous Retroviruses, Drosophila Proteins
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