Motor Neuron Disease-Associated Loss of Nuclear TDP-43 Is Linked to DNA Double-Strand Break Repair Defects

Mitra, Joy; Guerrero, Erika N.; Hegde, Pavana M.; Liachko, Nicole F.; Vasquez, Velmarini; Wang, Haibo; Gao, Junling; Pandey, Arvind; Taylor, J. Paul; Kraemer, Brian C.; Wu, Ping; Boldogh, István; Garruto, Ralph M.; Mitra, Sankar; Rao, K. S.; Hegde, Muralidhar L.

doi:10.2139/ssrn.3155763

Cited by 52 publications

(98 citation statements)

References 31 publications

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“…TDP-43, on the other hand, binds to GUrich sequences and can compete with termination factors for UG-rich sequences downstream of the polyadenylation signal (66,67). Furthermore, both FUS and TDP-43 are known to suppress the buildup of transcription-associated DNA damage (52,(68)(69)(70)(71)(72). Given that ALS or FTD develops after decades of life, we hypothesize that the accumulation of DNA damage due to the buildup of R-loops at transcription terminators in post-mitotic neurons contributes to neurodegenerative pathology.…”

Section: Discussionmentioning

confidence: 99%

Regulation of transcription termination by FUS and TDP-43

Zhao

et al. 2019

Preprint

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The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. We previously found that symmetrical dimethylation (me2s) of a CTD Arginine residue (R1810 in human) causes recruitment of the Tudor domain of SMN, which interacts with Senataxin. SMN is mutated in spinal muscular atrophy (SMA), and Senataxin is sometimes mutated in Amyotrophic Lateral Sclerosis (ALS). R1810me2s and SMN, like Senataxin, are important for resolving R-loops (DNA:RNA hybrids) at transcription terminators. FUS and TDP-43 (TARDBP) are DNA/RNA binding proteins that are sometimes mutated in ALS and FTD (Frontotemporal dementia). Here we show that TDP-43 and, to some extent, FUS are recruited by the R1810me2s-SMN pathway. Defects in FUS and TDP-43 recruitment influence RNAPII termination and R-loop accumulation, leading to elevated DNA damage at terminators that may contribute to neurodegenerative disorders like ALS and FTD.

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Section: Discussionmentioning

confidence: 99%

Regulation of transcription termination by FUS and TDP-43

Zhao

et al. 2019

Preprint

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“…concentration. If complete ablation of TDP-43 is embryonically lethal, conditional knock-out and limited knocking-down of TDP-43 results in neuron degeneration (Iguchi et al, 2013;Mitra et al, 2019;Wu et al, 2012).…”

Section: Ftld-tdp Is the Most Common Neuropathologic Type Of Ftld Andmentioning

confidence: 99%

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

Pasetto

Grassano

Pozzi

et al. 2020

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Frontotemporal dementia (FTD) is a common cause of early-onset dementia, characterized by frontotemporal lobar degeneration and considerable clinical, genetic and neuropathological heterogeneity. Several mouse models of FTD have been generated targeting genes with known pathogenic roles. However, each of these models recapitulates only certain aspects of the human disease. Cyclophilin A (PPIA) is a multifunctional protein abundantly expressed in the brain, with double-edged functions. Intracellularly, it is mainly protective as a foldase and molecular chaperone with scaffolding properties. Extracellularly, it behaves as a proinflammatory cytokine able to activate an aberrant inflammatory response. In a previous work, we found that PPIA governs TDP-43 functions and its deficiency exacerbates disease in a mouse model of ALS.Selective inhibition of extracellular PPIA rescued motor neurons and increased survival. To decipher PPIA's functions in the central nervous system, we planned a deep neuropathological and behavioral characterization of PPIA knock-out (PPIA-/-) mice throughout their lifespan. They develop a neurodegenerative disease that recapitulates key features of the behavioral variant of FTD associated with TDP-43 pathology. PPIA-/-mice present progressive hippocampal and cortex atrophy, with neuronal death and clear-cut TDP-43 pathology that include fragmentation, hyperphosphorylation, and cytoplasmic mislocalization/nuclear clearing. Mice exhibit increased disinhibition, defects in social behavior, but no memory and motor impairment. On a molecular level, our findings indicate that PPIA is involved in multiple genes and pathways that have a dominant protective effect in the brain, and is fundamental for TDP-43 function. Considering that an impaired interaction of TDP-43 with PPIA has been observed in ALS/FTD patients, the PPIA-/-mouse is a useful experimental model to investigate the mechanism at the basis of TDP-43 pathology and develop novel therapeutic approaches for ALS/FTD and possibly other TDP-43 proteinopathies.

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“…Recent studies proved that increased cytosolic 4 sequestration of the poly-ubiquitinated and aggregated forms of mutant TDP-43 correlates with higher levels of DNA strand breaks, activation of DDR factors such as phospho-ataxiatelangiectasia mutated (ATM), phospho-53BP1, γH2AX in SH-SY5Y lines expressing wildtype (WT) or Q331K-mutant TDP-43 [21]. TDP-43 depletion leads to increased sensitivity to various forms of DNA damage and mutation in the C-terminus glycine-rich lowcomplexity region (LC domain) associates with the loss of its nuclear function [22]. In addition, TDP-43 colocalizes with active RNA polymerase II at sites of DNA damage along with the DDR protein, BRCA1, participating in the prevention and/or repair of R loopassociated DNA damage [23].…”

Section: Introductionmentioning

confidence: 99%

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

Giannini¹,

Sproviero²,

Bayona-Feliú

et al. 2020

Preprint

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TDP-43 is a DNA and RNA binding protein involved in RNA processing and with structural resemblance to heterogeneous ribonucleoproteins (hnRNPs), whose depletion sensitizes neurons to double strand DNA breaks (DSBs). Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder, in which 97% of patients are familial and sporadic cases associated with TDP-43 proteinopathies and conditions clearing TDP-43 from the nucleus, but we know little about the molecular basis of the disease. Here, we prove that mislocalization of mutated TDP-43 (A382T) in transfected neuronal SH-SY5Y and lymphoblastoid cell lines (LCLs) from an ALS patient cause R-loop accumulation, and R loop-dependent increased DSBs and Fanconi Anemia repair centers. Similar results were observed in a non-neuronal model of HeLa cells depleted of TDP-43. These results uncover a new role of TDP-43 in the control of co-transcriptional R-loops and the maintenance of genome integrity by preventing harmful R-loop accumulation. Our findings thus link TDP-43 pathology to increased R-loops and R loop-mediated DNA damage opening the possibility that R-loop modulation in TDP-43-defective cells might help develop ALS therapies.

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Motor Neuron Disease-Associated Loss of Nuclear TDP-43 Is Linked to DNA Double-Strand Break Repair Defects

Cited by 52 publications

References 31 publications

Regulation of transcription termination by FUS and TDP-43

Regulation of transcription termination by FUS and TDP-43

Defective cyclophilin A induces TDP-43 proteinopathy: implications for amyotrophic lateral sclerosis and frontotemporal dementia

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

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