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.

RNA Degradation in Neurodegenerative Disease

“…This suggests that TDP43 normally regulates TE expression, and the loss of functional TDP43 in FTD results in TE overexpression [328]. This is further supported by the finding that TEs are derepressed in ALS/FTD models involving TDP43 overexpression or knockdown [328,329], suggesting that TE dysregulation may contribute to neurodegeneration in ALS and FTD. This may occur through activation of DNA damage-mediated programmed cell death due to the large scale deletions and genomic rearrangements that result from de-repressed TEs [329], and there is some evidence to suggest that TDP43 pathology impairs siRNA-mediated gene silencing, an essential system that normally protects the genome from retrotransposons [329]…”

ALSUntangled 45: Antiretrovirals

“…The second possibility is that HERV protein levels are mediated by TAR DNA binding protein 43 (TDP-43), which has an important role in ALS pathophysiology (17) and has been shown to be increased in the cerebrospinal fluid (18)(19)(20)(21)(22) and blood (23) of some PALS. Based on experiments in cultured human cells, Drosophila (fruit fly) and mice TDP-43 models, it is possible that HERV RT protein levels are being increased by TDP-43 through a not yet clear mechanism (11,(24)(25)(26). Interestingly, HIV infection of the CNS also leads to neuroinflammation, increased TDP-43 expression, and increased HERV expression (27).…”

“…In a Drosophila model of ALS expressing human TDP-43 (hTDP-43) (46), the transgenic fruit flies have progressive neurological degeneration characterized by brain cell death, progressive motor impairment, and a substantially reduced lifespan (25,46). Using this model, one group found that hTDP-43 selectively expressed in the flies' glial cells, but not when selectively expressed in neurons, caused a Drosophila endogenous retrovirus similar to HERV type K, named gypsy, to be expressed in higher quantities.…”

“…In flies with hTDP-43 expressing glia, inhibition of gypsy expression by interfering RNA caused the flies to have a lifespan approximately 75% of normal flies, which is an approximately 5-fold increase in lifespan relative to negative control hTDP-43 flies and untreated hTDP-43 flies, which had lifespans approximately 15% of normal flies. Treatment of the same type of hTDP-43 fly with each of the antiretroviral NRTIs stavudine and zidovudine resulted in a small statistically significant increase in lifespan relative to untreated controls (25). This study was well-designed with negative controls, but the meaning of these results to human ALS is difficult to interpret, because they are based on an analog endogenous retrovirus in a nonvertebrate animal and utilized small experimental groups of 6-12 flies.…”

An ultra-fast and scalable quantification pipeline for transposable elements from next generation sequencing data

“…5 Recent development of high-throughput Next Generation Sequencing (NGS) technologies, like RNA-seq, enables genome-wide study for TEs. [6][7][8][9] Toward this end, several algorithms and pipelines were proposed to analyze reads files from TE studies. [10][11][12][13][14][15][16] However, most of the tools share some common limitations: 1) discordant read mapping due to increased chance of multiple mapping in repetitive elements from TEs in the same clade, 2) limited scalability for large-scale analysis, and 3) small coverage for the entire TEs defined in the human genome, i.e., a tool used in [16] only considered LINE 1 (Long Interspersed Nuclear Element 1) elements.…”