Nucleocytoplasmic transport in<i>C9orf72-</i>mediated ALS/FTD

Zhang, Ke; Grima, Jonathan C.; Rothstein, Jeffery D.; Lloyd, Thomas E.

doi:10.1080/19491034.2016.1172152

Cited by 29 publications

(27 citation statements)

References 36 publications

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“…R-DPRs inhibit NMD via translational repression. G 4 C 2 repeats and R-DPRs have also been associated with nucleocytoplasmic transport defects 33 . If nuclear export of RNA is delayed, both NMD targets and non-targets would be expected accumulate in the nucleus.…”

Section: Resultsmentioning

confidence: 99%

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

et al. 2020

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Expansion of an intronic (GGGGCC) n repeat region within the C9orf72 gene is a main cause of familial amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). A hallmark of c9ALS/FTD is the accumulation of misprocessed RNAs, which are often targets of cellular RNA surveillance. Here, we show that RNA decay mechanisms involving upstream frameshift 1 (UPF1), including nonsense-mediated decay (NMD), are inhibited in c9ALS/FTD brains and in cultured cells expressing either of two arginine-rich dipeptide repeats (R-DPRs), poly(GR) and poly(PR). Mechanistically, although R-DPRs cause the recruitment of UPF1 to stress granules, stress granule formation is independent of NMD inhibition. Instead, NMD inhibition is primarily a result from global translational repression caused by R-DPRs. Overexpression of UPF1, but none of its NMD-deficient mutants, enhanced the survival of neurons treated by R-DPRs, suggesting that R-DPRs cause neurotoxicity in part by inhibiting cellular RNA surveillance.

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Section: Resultsmentioning

confidence: 99%

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

et al. 2020

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“…The transport of mRNA and proteins between the nucleus and the cytoplasm has emerged as a critical cellular pathway in neurodegenerative diseases 24,28,30,61,62 . Here, we developed an approach to assess how the repeat expansion in C9orf72 impacts the subcellular N/C distribution of proteins.…”

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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“…Thus, it is possible that C9 DPR proteins may further impede mRNA transport throughout other areas of the cell via disruptions in nucleo/cytoplasmic transport. It is hypothesized that these defects may contribute to the mislocalization of key proteins such as TDP-43 early in the cascade of pathogenic events (Zhang K. et al, 2016 ). In turn, this could further impact RNA metabolism.…”

Section: C9orf72 Rna Based Mechanisms In Alsmentioning

confidence: 99%

Failure to Deliver and Translate—New Insights into RNA Dysregulation in ALS

Coyne

Zaepfel

Zarnescu

2017

Front. Cell. Neurosci.

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Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disease affecting both upper and lower motor neurons. The molecular mechanisms underlying disease pathogenesis remain largely unknown. Multiple genetic loci including genes involved in proteostasis and ribostasis have been linked to ALS providing key insights into the molecular mechanisms underlying disease. In particular, the identification of the RNA binding proteins TDP-43 and fused in sarcoma (FUS) as causative factors of ALS resulted in a paradigm shift centered on the study of RNA dysregulation as a major mechanism of disease. With wild-type TDP-43 pathology being found in ~97% of ALS cases and the identification of disease causing mutations within its sequence, TDP-43 has emerged as a prominent player in ALS. More recently, studies of the newly discovered C9orf72 repeat expansion are lending further support to the notion of defects in RNA metabolism as a key factor underlying ALS. RNA binding proteins are involved in all aspects of RNA metabolism ranging from splicing, transcription, transport, storage into RNA/protein granules, and translation. How these processes are affected by disease-associated mutations is just beginning to be understood. Considerable work has gone into the identification of splicing and transcription defects resulting from mutations in RNA binding proteins associated with disease. More recently, defects in RNA transport and translation have been shown to be involved in the pathomechanism of ALS. A central hypothesis in the field is that disease causing mutations lead to the persistence of RNA/protein complexes known as stress granules. Under times of prolonged cellular stress these granules sequester specific mRNAs preventing them from translation, and are thought to evolve into pathological aggregates. Here we will review recent efforts directed at understanding how altered RNA metabolism contributes to ALS pathogenesis.

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Nucleocytoplasmic transport inC9orf72-mediated ALS/FTD

Cited by 29 publications

References 36 publications

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

C9orf72 arginine-rich dipeptide repeats inhibit UPF1-mediated RNA decay via translational repression

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

Failure to Deliver and Translate—New Insights into RNA Dysregulation in ALS

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