Abnormal RNA stability in amyotrophic lateral sclerosis

Tank, Elizabeth M.H.; Figueroa‐Romero, Claudia; Hinder, Lucy M.; Bedi, Karan; Archbold, Hilary C.; Li, Xingli; Weskamp, Kaitlin; Safren, Nathaniel; Paez-Colasante, Ximena; Pacut, Crystal; Thumma, Saritha C.; Paulsen, Michelle T.; Guo, Kai; Hur, Junguk; Ljungman, Mats; Feldman, Eva L.; Barmada, Sami J.

doi:10.1038/s41467-018-05049-z

Cited by 130 publications

(129 citation statements)

References 79 publications

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“…As consequence of RNA instability in iPSCs it was detected an increase of cytoplasmic ribosome proteins including RPL13A, suggested as cellular compensatory response for preservation of protein synthesis capacity. Moreover, the analysis of 3′UTRs of transcripts in the same cells showed a high enrichment in motifs recognized by RBPs and involved in the formation of cytoplasmic inclusions, that in turn exhibited an alteration of their stability [58]. We do not believe that the particular effect observed in accumulation of R-loops in RPL13A is related to these phenotypes, since ribosomal protein genes are highly transcribed, thus favouring R-loop formation.…”

Section: Discussionmentioning

confidence: 80%

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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Section: Discussionmentioning

confidence: 80%

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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“…Moreover, a number of studies have extensively characterized RNA metabolism defects in ALS 69 . These include RNA instability 70 , defective RNA splicing in mutant TDP-43 and FUS models [71][72][73] , as well as within postmortem patient brain samples from C9orf72 and sporadic ALS cases 74 .…”

Section: Discussionmentioning

confidence: 99%

“…We discovered that NMD is protective in C9 model systems. At the same time, the cytosolic accumulation of TDP-43 and thus erroneous mRNA metabolism is a unifying pathological feature amongst ALS patients 1,70 , suggesting that the NMD pathway and its regulatory elements could represent a therapeutic approach that could be broadly relevant for ALS and FTD. Fig.…”

Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Ortega

Daley

Kour

et al. 2019

Preprint

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The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by the C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift towards a more cytosolic proteome in C9-HRE cells. Amongst these was ETF1, which regulates translation termination and nonsense-mediated decay (NMD). ETF1 accumulates within elaborate nuclear envelope invaginations in patient iPSC-neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of ETF1 and the NMD-driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegenerationassociated repeat expansion mutations and highlight ETF1 and NMD as therapeutic targets in C9orf72-associated ALS/FTD. KEYWORDSAmyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), C9orf72, ETF1, nonsense mediated decay (NMD), UPF1, nucleocytoplasmic proteome, iPSCs, motor neurons. through three non-exclusive mechanisms 5-8 . Several reports have shown that C9orf72 expression is decreased in patients suggesting that haploinsufficiency contributes to pathogenesis 9, 10 . Gain-of-function neurotoxic effects occur through the production of aberrant C9-HRE RNA molecules 11 , as well as through dipeptide repeat proteins (DPRs) translated by a non-ATG dependent mechanism from the HRE 12, 13 . The repeat is bi-directionally transcribed and corresponding RNA sense and antisense molecules are detected by fluorescence in situ hybridization (FISH) as predominantly nuclear RNA foci in patient cells and tissue 11,13,14 . Moreover, five C9-HRE DPRs (GA, GP, GR, PR, PA) have been detected with antigen-specific antibodies in patient samples where they accumulate in cytoplasmic and nuclear aggregates in the frontal and motor cortex as well as the spinal cord 15,16 .While the relative contribution of loss-of-function effects, as well as the dominant source of toxic gain-of-function effects (RNA or DPRs) is still an open-ended question, substantial and converging evidence suggests that the C9-HRE disrupts the balance of proteins that are transported between the nucleus and the cytoplasm. The long C9-RNA that is transcribed from the repeat expansion binds and sequesters RNA-binding proteins in the nucleus 11 . The argininerich GR and PR C9-DPRs bind and sequester a number of proteins with low complexity domains that assemble into membrane-less organelles through liquid-liquid phase separation 17, 18 . These include RNA granules, nucleoli and various components of the nuclear pore complex (NPC). Consequently, a series of groundbreaking genetic studies in C9-HRE Drosophila and yeast mod...

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“…Healthy/Control iPSC lines, provided by Dr. Sami Barmada, were created and characterized as before (Tank et al ., 2018). Two lines from fALS patients carrying the C9orf72 mutation, and two lines from healthy controls, were used for all experiments.…”

Section: Methodsmentioning

confidence: 99%

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Maimon

Ankol

Weissova

et al. 2019

Preprint

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29Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease 30 with selective dysfunction; it causes the death of motor neurons (MNs). In spite of 31 some progress, currently no effective treatment is available for ALS. Before such 32 treatment can be developed, a more thorough understanding of ALS pathogenesis is 33 required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS 34 pathology via secretion of destabilizing factors such as Sema3A; these factors trigger 35 axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on 36 the molecular mechanism by which muscle contribute to MNs loss in ALS. We 37 identified CRMP4 as part of a retrograde death signal generated in response to 38 muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A 39 induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1 G93A ) 40 and human-derived (C9orf72) ALS models. Introducing peptides that interfere with 41 CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN 42 loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN 43 loss in ALS. 44 45 46 Summary 47 Maimon et al. identify a novel retrograde death mechanism that contribute to MN loss 48 in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the 49 axon.50 51 52 53 105 Strittmatter, 2007). The canonical signaling events of CRMPs during Semaphorin 106 signaling involve their phosphorylation via GTPase activity, which further leads to 107 microtubule destabilization and axon retraction (Sasaki et al., 2002; Yamashita and 108 5 Goshima , 2012; Balastik et al., 2015). In addition to their role in mediating Sema3A 109 intrinsic responses, CRMPs were also reported to bind dynein and kinesin, and 110 modulate their function (Arimura et al., 2009; Rahajeng et al., 2010). Several studies 111 further demonstrated the involvement of CRMPs in neurodegenerative diseases 112 (Charrier et al., 2003; Yamashita and Goshima, 2012; Nagai, Baba and Ohshima, 113 2017). Specifically, CRMP4 expression levels were previously found to be elevated in 114 the SOD1 G93A mouse spinal cord, and were suggested to hamper MN health (Duplan 115 et al., 2010; Valdez et al., 2012; Nagai et al., 2015). However, the mechanism underline 116 the involvement of CRMP4 mediating cell death and its role in other ALS model is still 117 elusive. Moreover, mutations in CRMP4 were associated with ALS patients (Blasco et 118 al., 2013). 119 120 Here, we identified a novel retrograde death signal, triggered by Sema3A, which 121 facilitates MN loss in both murine and human ALS models. This process is mediated 122 by the formation of CRMP4-Dynein complex along diseased axons. Interfering with the 123 binding of CRMP4 to Dynein by using short blocking peptides rescues Sema3A-124 dependent MN loss in these ALS models. 125 126 Results 127 128 SOD G93A MNs and muscle co-cultures enhance MN loss 129 MN cell death is a key process in ALS pathology. Taking into consideratio...

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Abnormal RNA stability in amyotrophic lateral sclerosis

Cited by 130 publications

References 79 publications

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

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

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

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