title: Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS.
abstract: 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.
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Lisa
authors.identifier: 0000-0002-2413-9416
authors.initials: L
authors.lastname: Krug
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Nabanita
authors.initials: N
authors.lastname: Chatterjee
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Rebeca
authors.identifier: 0000-0001-5821-7630
authors.initials: R
authors.lastname: Borges-Monroy
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Stephen
authors.initials: S
authors.lastname: Hearn
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Wen-Wei
authors.identifier: 0000-0001-8183-213X
authors.initials: WW
authors.lastname: Liao
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Kathleen
authors.initials: K
authors.lastname: Morrill
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.|Department of Biology, Farmingdale State College, Farmingdale, NY United States of America.
authors.forename: Lisa
authors.initials: L
authors.lastname: Prazak
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Nikolay
authors.initials: N
authors.lastname: Rozhkov
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Delphine
authors.initials: D
authors.lastname: Theodorou
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
authors.forename: Molly
authors.initials: M
authors.lastname: Hammell
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.|Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.|Department of Anesthesiology, Stony Brook School of Medicine, Stony Brook, New York, United States of America.|Department of Neurobiology and Behavior, Stony Brook School of Medicine, Stony Brook, New York, United States of America.
authors.forename: Josh
authors.initials: J
authors.lastname: Dubnau
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics* / Q000378:metabolism / Q000648:ultrastructure; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D018626:Retroelements / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004268:DNA-Binding Proteins; D018626:Retroelements; C000598624:TARDBP protein, human