TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Giannini, Marta; Sproviero, Daisy; Bayona-Feliú, Aleix; Cereda, Cristina; Aguilera, Andrés

doi:10.1101/2020.05.10.086652

Cited by 9 publications

(2 citation statements)

References 67 publications

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“…Besides its RNA-regulatory roles, TDP-43 is also implicated in DNA damage repair. TDP-43 depletion causes an accumulation of DNA double-strand breaks (DSBs), while TDP-43 overexpression is protective against DSBs [16,[74][75][76][77]. TDP-43 is rapidly recruited at DSB sites upon induction of DNA damage to stably interact with factors regulating DNA damage response and non-homologous end joining [74,75].…”

Section: Nuclear Bodies (Nbs)mentioning

confidence: 99%

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Asakawa

Handa

Kawakami

2021

Cell. Mol. Life Sci.

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Transactive response DNA-binding protein 43 kDa (TDP-43) encoded by the TARDBP gene is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) that regulates multiple steps of RNA metabolism, and its cytoplasmic aggregation characterizes degenerating motor neurons in amyotrophic lateral sclerosis (ALS). In most ALS cases, cytoplasmic TDP-43 aggregation occurs in the absence of mutations in the coding sequence of TARDBP. Thus, a major challenge in ALS research is to understand the nature of pathological changes occurring in wild-type TDP-43 and to explore upstream events in intracellular and extracellular milieu that promote the pathological transition of TDP-43. Despite the inherent obstacles to analyzing TDP-43 dynamics in in vivo motor neurons due to their anatomical complexity and inaccessibility, recent studies using cellular and animal models have provided important mechanistic insights into potential links between TDP-43 and motor neuron vulnerability in ALS. This review is intended to provide an overview of the current literature on the function and regulation of TDP-43-containing RNP granules or membraneless organelles, as revealed by various models, and to discuss the potential mechanisms by which TDP-43 can cause selective vulnerability of motor neurons in ALS.

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Section: Nuclear Bodies (Nbs)mentioning

confidence: 99%

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Asakawa

Handa

Kawakami

2021

Cell. Mol. Life Sci.

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“…Therefore, the results obtained in C2C12 suggest another possible mechanism on how TDP-43 may control gene expression in muscle in an indirect fashion and eventually participate in disease. Recently, loss of TDP-43 was associated with increased genomic instability and R-loop formation (Giannini et al, 2020;Wood et al, 2020) possibly through mechanisms involving Poldip3, which has been shown to play a role in maintaining genome stability and preventing R-loop accumulation at sites of active replication (Björkman et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Cell environment shapes TDP-43 function: implications in neuronal and muscle disease

Šušnjar

Škrabar

Brown

et al. 2021

Preprint

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TDP-43 aggregation and redistribution have been recognised as a hallmark of amyotrophic lateral sclerosis, frontotemporal dementia and other neurological disorders. While TDP-43 has been studied extensively in neuronal tissues, TDP-43 inclusions have also been described in the muscle of inclusion body myositis patients, highlighting the need to understand the role of TDP-43 beyond the central nervous system. Using RNA-seq we performed the first direct comparison of TDP-43-mediated transcription and alternative splicing in muscle (C2C12) and neuronal (NSC34) mouse cells. Our results clearly show that TDP-43 displays a tissue-characteristic behaviour targeting unique transcripts in each cell type. This is not due to variable transcript abundance but rather due to cell-specific expression of RNA-binding proteins, which influences TDP-43 performance. Among splicing events commonly dysregulated in both cell lines, we identified some that are TDP-43-dependent also in human cells and show that inclusion levels of these alternative exons appear to be differentially altered in affected tissues of FTLD and IBM patients. We therefore propose that TDP-43 dysfunction, reflected in aberrant splicing, contributes to disease development but it does so in a tissue- and disease-specific manner.

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Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

Joachimiak

Ciesiolka

Figura

et al. 2022

Cells

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Repeat expansion diseases are a group of more than 40 disorders that affect mainly the nervous and/or muscular system and include myotonic dystrophies, Huntington’s disease, and fragile X syndrome. The mutation-driven expanded repeat tract occurs in specific genes and is composed of tri- to dodeca-nucleotide-long units. Mutant mRNA is a pathogenic factor or important contributor to the disease and has great potential as a therapeutic target. Although repeat expansion diseases are quite well known, there are limited studies concerning polyadenylation events for implicated transcripts that could have profound effects on transcript stability, localization, and translation efficiency. In this review, we briefly present polyadenylation and alternative polyadenylation (APA) mechanisms and discuss their role in the pathogenesis of selected diseases. We also discuss several methods for poly(A) tail measurement (both transcript-specific and transcriptome-wide analyses) and APA site identification—the further development and use of which may contribute to a better understanding of the correlation between APA events and repeat expansion diseases. Finally, we point out some future perspectives on the research into repeat expansion diseases, as well as APA studies.

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TDP-43 deficiency links Amyotrophic Lateral Sclerosis with R-loop homeostasis and R loop-mediated DNA damage

Cited by 9 publications

References 67 publications

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Multi-phaseted problems of TDP-43 in selective neuronal vulnerability in ALS

Cell environment shapes TDP-43 function: implications in neuronal and muscle disease

Implications of Poly(A) Tail Processing in Repeat Expansion Diseases

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