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Curr Biol. 2019 Oct 7;29(19):3135-3152.e4. doi: 10.1016/j.cub.2019.07.071. Epub 2019 Sep 5.

The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration.

Author information

1
Department of Anesthesiology, Stony Brook School of Medicine, NY 11794, USA.
2
Department of Anesthesiology, Stony Brook School of Medicine, NY 11794, USA; Department of Neurobiology and Behavior, Stony Brook University, NY 11794, USA. Electronic address: joshua.dubnau@stonybrook.edu.

Abstract

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.

KEYWORDS:

DNA damage; Drosophila; ERV; TDP-43; amyotrophic lateral sclerosis; endogenous retrovirus; frontotemporal dementia; neurodegeneration; retrotransposon; transposon

PMID:
31495585
DOI:
10.1016/j.cub.2019.07.071

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