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

Krug, L., Chatterjee, N., Borges-Monroy, R., Hearn, S., Liao, W. W., Morrill, K., Prazak, L., Rozhkov, N., Theodorou, D., Hammell, M., Dubnau, J. (2017) Retrotransposon activation contributes to neurodegeneration in a Drosophila TDP-43 model of ALS. PLoS Genet, 13 (3). e1006635. ISSN 1553-7390

URL: https://www.ncbi.nlm.nih.gov/pubmed/28301478
DOI: 10.1371/journal.pgen.1006635

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.

Item Type: Paper
Subjects: organism description > animal > insect > Drosophila
diseases & disorders > neurodegenerative diseases > ALS
diseases & disorders > neurodegenerative diseases
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA expression > transposable elements
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transposons
CSHL Authors:
Communities: CSHL labs > Dubnau lab
CSHL labs > Hammell M. lab
Depositing User: Matt Covey
Date Deposited: 17 Mar 2017 20:26
Last Modified: 07 Sep 2017 18:20
Related URLs:
Dataset ID:
URI: http://repository.cshl.edu/id/eprint/34273

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