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dc.contributor.authorKrug, Lisa
dc.contributor.authorChatterjee, Nabanita
dc.contributor.authorBorges-Monroy, Rebeca
dc.contributor.authorHearn, Stephen
dc.contributor.authorLiao, Wen-Wei
dc.contributor.authorMorrill, Kathleen
dc.contributor.authorPrazak, Lisa
dc.contributor.authorRozhkov, Nikolay
dc.contributor.authorTheodorou, Delphine
dc.contributor.authorHammell, Molly
dc.contributor.authorDubnau, Josh
dc.date.accessioned2019-08-27T18:34:19Z
dc.date.available2019-08-27T18:34:19Z
dc.date.issued2017-03-16
dc.identifier.otherhttp://dx.doi.org/10.1371/journal.pgen.1006635
dc.identifier.urihttp://hdl.handle.net/1951/70894
dc.description© 2017 Krug et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en_US
dc.description.abstractAmyotrophic 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 derepression 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.en_US
dc.description.sponsorshipThis work was supported by NIH R01 grant NS067690 and NIH R01 grant NS091748 awarded to JD, and by external research awards to JD from DART Neuroscience LLC. We also are grateful for generous support to JD and MH from Ride For Life, Inc. The Rita Allen foundation provided support to MH. In addition, LK was supported by NIH training grant 5T32GM065094. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.en_US
dc.language.isoen_USen_US
dc.publisherPLOS Geneticsen_US
dc.subjectAmyotrophic lateral sclerosis (ALS)en_US
dc.subjectfrontotemporal lobar degeneration (FTLD)en_US
dc.subjectneurodegenerative disordersen_US
dc.titleRetrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALSen_US
dc.typeArticleen_US


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