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PLoS Genet. 2017 Mar 16;13(3):e1006635. doi: 10.1371/journal.pgen.1006635. eCollection 2017 Mar.

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

Author information

1
Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
2
Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY, United States of America.
3
Department of Biology, Farmingdale State College, Farmingdale, NY United States of America.
4
Department of Anesthesiology, Stony Brook School of Medicine, Stony Brook, New York, United States of America.
5
Department of Neurobiology and Behavior, Stony Brook School of Medicine, Stony Brook, New York, United States of America.

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.

PMID:
28301478
PMCID:
PMC5354250
DOI:
10.1371/journal.pgen.1006635
[Indexed for MEDLINE]
Free PMC Article

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