Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS

• Published in: PLoS genetics 2017-03, Vol.13 (3), p.e1006635-e1006635
• Main Authors: Krug, Lisa, Chatterjee, Nabanita, Borges-Monroy, Rebeca, Hearn, Stephen, Liao, Wen-Wei, Morrill, Kathleen, Prazak, Lisa, Rozhkov, Nikolay, Theodorou, Delphine, Hammell, Molly, Dubnau, Josh
• Format: Article
• Language: English
• Subjects: Activation; Amyotrophic lateral sclerosis; Amyotrophic Lateral Sclerosis - genetics; Amyotrophic Lateral Sclerosis - metabolism; Animals; Animals, Genetically Modified; Apoptosis; Bioinformatics; Biology; Biology and life sciences; Cell cycle; Cell death; Computer industry; Deoxyribonucleic acid; Disease; Disease Models, Animal; DNA; DNA damage; DNA-binding protein; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Drosophila; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila melanogaster - ultrastructure; Frontotemporal Lobar Degeneration - genetics; Frontotemporal Lobar Degeneration - metabolism; Fruit flies; Funding; Gene Expression Profiling; Genetic aspects; Genomes; Humans; Immunohistochemistry; Insects; Laboratories; Male; Medicine and Health Sciences; Memory; Microscopy, Confocal; Microscopy, Electron, Transmission; Neurodegeneration; Neurodegenerative Diseases - genetics; Neurodegenerative Diseases - metabolism; Neuroglia - metabolism; Neurological diseases; Neurons; Neurons - metabolism; Neurosciences; Proteins; Research and Analysis Methods; Retroelements - genetics; Retrotransposons; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Toxicity; Value added resellers
• ISSN: 1553-7404; 1553-7390; 1553-7404
• DOI: 10.1371/journal.pgen.1006635

Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are two incurable neurodegenerative disorders that exist on a symptomological spectrum and share both genetic underpinnings and pathophysiological hallmarks. Functional abnormality of TAR DNA-binding protein 43 (TDP-43), an aggregation-prone RNA and DNA binding protein, is observed in the vast majority of both familial and sporadic ALS cases and in ~40% of FTLD cases, but the cascade of events leading to cell death are not understood. We have expressed human TDP-43 (hTDP-43) in Drosophila neurons and glia, a model that recapitulates many of the characteristics of TDP-43-linked human disease including protein aggregation pathology, locomotor impairment, and premature death. We report that such expression of hTDP-43 impairs small interfering RNA (siRNA) silencing, which is the major post-transcriptional mechanism of retrotransposable element (RTE) control in somatic tissue. This is accompanied by de-repression of a panel of both LINE and LTR families of RTEs, with somewhat different elements being active in response to hTDP-43 expression in glia versus neurons. hTDP-43 expression in glia causes an early and severe loss of control of a specific RTE, the endogenous retrovirus (ERV) gypsy. We demonstrate that gypsy causes the degenerative phenotypes in these flies because we are able to rescue the toxicity of glial hTDP-43 either by genetically blocking expression of this RTE or by pharmacologically inhibiting RTE reverse transcriptase activity. Moreover, we provide evidence that activation of DNA damage-mediated programmed cell death underlies both neuronal and glial hTDP-43 toxicity, consistent with RTE-mediated effects in both cell types. Our findings suggest a novel mechanism in which RTE activity contributes to neurodegeneration in TDP-43-mediated diseases such as ALS and FTLD.