The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration

Chang, Yung-Heng; Dubnau, Josh

doi:10.1016/j.cub.2019.07.071

Cited by 49 publications

(95 citation statements)

References 82 publications

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“…Moreover, the connection between TDP-43 and transposable elements has only recently been explored. While previous studies have linked TDP-43 to transposon binding in human cells and to transposon regulation in animal models (Chang and Dubnau, 2019;Krug et al, 2017;Li et al, 2015;Liu et al, 2019), we show that TDP-4-bound transposon transcripts are de-silenced in human cells and demonstrate that these same targets are de-silenced in a subset of human ALS patients. Additional mechanisms for transposon de-silencing in ALS patients with C9orf72 repeat expansions have been suggested (Pereira et al, 2018;Prudencio et al, 2017;Zhang et al, 2019), although we note that C9orf72 status was not strongly associated with the ALS-TE group in this study.…”

Section: Discussioncontrasting

confidence: 60%

“…TDP-43 has known roles in RNA splicing, stability, and small RNA biogenesis (Cohen et al, 2011). Recently, several studies have suggested that TDP-43 also plays a role in regulating the activity of retrotransposons (Chang and Dubnau, 2019;Krug et al, 2017;Li et al, 2015;Saldi et al, 2014). Retrotransposons, a subset of transposable elements (TEs), are genomic parasites capable of inserting new copies of themselves throughout the genome by a process called retrotransposition.…”

Section: Introductionmentioning

confidence: 99%

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Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

et al. 2019

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AUTHOR CONTRIBUTIONS O.H.T., M.G.H., and J.D. designed the study. N.V.R. designed and performed the experiments identifying TDP-43 targets in SH-SY5Y cells. R.S. designed and performed the experiments on the UCSD ALS patient samples. J.R. provided the UCSD ALS patient samples and associated clinical and diagnostic data. In the NYGC ALS Consortium, members contributed ALS patient samples and clinical information. D.K. curated de-identified clinical data and C9orf72 genotype information. I.H. and N.P. coordinated study materials and processed samples for sequencing. S.F. oversees Consortium resources and data distribution. D.F. and H.P. designed the methodology, reviewed sample preparation and data quality, and coordinated the research activity of NYGC ALS Consortium postmortem core RNA-seq experiments. B.T.H. supervised the neuropathological analysis of the immunohistochemical staining results. L.W.O. coordinated the post-mortem tissue, slide, and data collection through the Target ALS Multicenter Post-Mortem Tissue Core and assisted in analysis of the immunohistochemical staining results. O.H.T. and M.G.H. analyzed the data. All authors contributed to the interpretation, writing, and editing of the manuscript.

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Section: Discussioncontrasting

confidence: 60%

Section: Introductionmentioning

confidence: 99%

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

et al. 2019

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“…Regarding that, we found that the expression of Dcr-2 in glial tissues was similarly able to revert the motility defects specified in TBPH-minus flies, the glial wrapping of motoneuron axons, and the non-autonomous formations of new synaptic branches (Fig. 4a, g-j) suggesting that the activation of the siRNA machinery positively contributed to the proper functioning of the glia, most probably, via the repression of different retrotransposons and/or by playing a role in the organization of the heterochromatin [42,43]. Regarding the molecular mechanisms, besides TBPH-mediated Dcr-2 regulation, we found that TBPH forms molecular complexes with Dcr-2 through physical interactions with the mRNA and the protein itself.…”

Section: Tbph Prevents Rte-mediated Neurodegeneration Via the Regulatmentioning

confidence: 89%

TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity

2020

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Background: Mutations in the small RNA-binding protein TDP-43 lead to the formation of insoluble cytoplasmic aggregates that have been associated with the onset and progression of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder affecting homeostasis of the motor system which is also characterized by aberrant expression of retrotransposable elements (RTEs). Although the TDP-43 function was shown to be required in the neurons and glia to maintain the organization of neuromuscular synapses and prevent denervation of the skeletal muscles, the molecular mechanisms involved in physiological dysregulation remain elusive. Here, we address this issue using a null mutation of the TDP-43 Drosophila homolog, TBPH. Results: Using genome-wide gene expression profiles, we detected a strong upregulation of RTE expression in TBPH-null Drosophila heads, while the genetic rescue of the TDP-43 function reverted these modifications. Furthermore, we found that TBPH modulates the small interfering RNA (siRNA) silencing machinery responsible for RTE repression. Molecularly, we observed that TBPH regulates the expression levels of Dicer-2 by direct protein-mRNA interactions in vivo. Accordingly, the genetic or pharmacological recovery of Dicer-2 activity was sufficient to repress retrotransposon activation and promote motoneuron axonal wrapping and synaptic growth in TBPH-null Drosophila. Conclusions: We identified an upregulation of RTE expression in TBPH-null Drosophila heads and demonstrate that defects in the siRNA pathway lead to RTE upregulation and motoneuron degeneration. Our results describe a novel physiological role of endogenous TDP-43 in the prevention of RTE-induced neurological alterations through the modulation of Dicer-2 activity and the siRNA pathway.

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“…Neuroinflammation with subsequent neurodegeneration can also result from a glia autonomous problem in dealing with DDR. Mutant human TDP43 expressed specifically in Drosophila glial cells causes DNA damage, elevated replication of retrotransposable elements (RTE) [ 139 ], and Gypsy endogenous retroviruses [ 140 ] and apoptosis in the nearby neurons. During their replication, the expression of RTE cDNA can lead to genome instability and accumulation of DSBs [ 141 ].…”

Section: Neuroinflammation and Ddr In Alsmentioning

confidence: 99%

The role of DNA damage response in amyotrophic lateral sclerosis

Sun

Curle

Haider

et al. 2020

Essays in Biochemistry

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Amyotrophic lateral sclerosis (ALS) is a rapidly disabling and fatal neurodegenerative disease. Due to insufficient disease-modifying treatments, there is an unmet and urgent need for elucidating disease mechanisms that occur early and represent common triggers in both familial and sporadic ALS. Emerging evidence suggests that impaired DNA damage response contributes to age-related somatic accumulation of genomic instability and can trigger or accelerate ALS pathological manifestations. In this review, we summarize and discuss recent studies indicating a direct link between DNA damage response and ALS. Further mechanistic understanding of the role genomic instability is playing in ALS disease pathophysiology will be critical for discovering new therapeutic avenues.

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The Gypsy Endogenous Retrovirus Drives Non-Cell-Autonomous Propagation in a Drosophila TDP-43 Model of Neurodegeneration

Cited by 49 publications

References 82 publications

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

Postmortem Cortex Samples Identify Distinct Molecular Subtypes of ALS: Retrotransposon Activation, Oxidative Stress, and Activated Glia

TDP-43 prevents retrotransposon activation in the Drosophila motor system through regulation of Dicer-2 activity

The role of DNA damage response in amyotrophic lateral sclerosis

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