Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE112931 | GEO | 2019/02/04
REPOSITORIES: GEO
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Project description:The major genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) is a C9orf72 G4C2 repeat expansion1,2. Proposed mechanisms by which the expansion causes c9FTD/ALS include toxicity from repeat-containing RNA and from dipeptide repeat proteins translated from these transcripts. To investigate the contribution of poly(GR) dipeptide repeat proteins to c9FTD/ALS pathogenesis in a mammalian in vivo model, we generated mice that expressed GFP-(GR)100 in the brain. GFP-(GR)100 mice developed age-dependent neurodegeneration, brain atrophy, and motor and memory deficits through the accumulation of diffuse, cytoplasmic poly(GR). Poly(GR) co-localized with ribosomal subunits and the translation initiation factor eIF3η in GFP-(GR)100 mice and, of importance, in c9FTD/ALS patients. Combined with the differential expression of ribosome-associated genes in GFP-(GR)100 mice, these findings demonstrate poly(GR)-mediated ribosomal distress. Indeed, poly(GR) inhibited canonical and non-canonical protein translation in HEK293T cells, and also induced the formation of stress granules and delayed their disassembly. These data suggest that poly(GR) contributes to c9FTD/ALS by impairing protein translation and stress granule dynamics, consequently causing chronic cellular stress and preventing cells from mounting an effective stress response. Decreasing poly(GR) and/or interrupting interactions between poly(GR) and ribosomal and stress granule-associated proteins may thus represent potential therapeutic strategies to restore homeostasis.
| S-EPMC6520050 | biostudies-literature
Project description:Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis
| PRJNA449525 | ENA
Project description:Purpose of reviewAn intronic G4C2 expansion mutation in C9orf72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Although there are currently no treatments for this insidious, fatal disease, intense research has led to promising therapeutic strategies, which will be discussed here.Recent findingsTherapeutic strategies for C9-ALS/FTD have primarily focused on reducing the toxic effects of mutant expansion RNAs or the dipeptide repeat proteins (DPRs). The pathogenic effects of G4C2 expansion transcripts have been targeted using approaches aimed at promoting their degradation, inhibiting nuclear export or silencing transcription. Other promising strategies include immunotherapy to reduce the DPRs themselves, reducing RAN translation, removing the repeats using DNA or RNA editing and manipulation of downstream disease-altered stress granule pathways. Finally, understanding the molecular triggers that lead to pheno-conversion may lead to opportunities that can delay symptomatic disease onset.SummaryA large body of evidence implicates RAN-translated DPRs as a main driver of C9-ALS/FTD. Promising therapeutic strategies for these devastating diseases are being rapidly developed with several approaches already in or approaching clinical trials.
| S-EPMC8678157 | biostudies-literature
Project description:GGGGCC repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). It has been reported that hexanucleotide repeat expansions in C9ORF72 produce five dipeptide repeat (DPR) proteins by an unconventional repeat-associated non-ATG (RAN) translation. Within the five DPR proteins, poly-PR and poly-GR that contain arginine are more toxic than the other DPRs (poly-GA, poly-GP, and poly-PA). Here, we demonstrated that poly-PR peptides transferred into cells by endocytosis in a clathrin-dependent manner, leading to endoplasmic reticulum stress and cell death. In SH-SY5Y cells and primary cortical neurons, poly-PR activated JUN amino-terminal kinase (JNK) and increased the levels of p53 and Bax. The uptake of poly-PR peptides by cells was significantly inhibited by knockdown of clathrin or by chlorpromazine, an inhibitor that blocks clathrin-mediated endocytosis. Inhibition of clathrin-dependent endocytosis by chlorpromazine significantly blocked the transfer of poly-PR peptides into cells, and attenuated poly-PR-induced JNK activation and cell death. Our data revealed that the uptake of poly-PR undergoes clathrin-dependent endocytosis and blockade of this process prevents the toxic effects of synthetic poly-PR peptides.
| S-EPMC6754483 | biostudies-literature
Project description:The expanded GGGGCC hexanucleotide repeat in the non-coding region of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There are three main disease mechanisms: loss of function of C9ORF72 protein, gain of function from the accumulation of sense and antisense (GGGGCC)n in RNA, and from the production of toxic dipeptides repeat proteins (DPRs) by non-AUG initiated translation. While many of the downstream mechanisms have been identified, the specific pathogenic pathway is still unclear. In this article, we provide an overview on the currently available literature and propose several hypotheses: (1) The pathogenesis of C9orf72-associated ALS/FTD, which cannot be explained by a single mechanism, involves a dual mechanism of both loss and gain of function. (2) The loss of function and gain of function can cause TDP-43 aggregation and damage nucleocytoplasmic transport. (3) Neurodegeneration can be caused by an accumulation of toxic substances in neurons themselves. In addition, we suggest that microglia may cause neurodegeneration by releasing inflammatory factors to neurons. Finally, we summarize several of the most promising treatment strategies.
| S-EPMC7492664 | biostudies-literature
Project description:In 2011, a hexanucleotide repeat expansion in the first intron of the C9orf72 gene was identified as the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The proposed disease mechanisms include loss of C9orf72 function and gain of toxicity from the bidirectionally transcribed repeat-containing RNAs. Over the last few years, substantial progress has been made to determine the contribution of loss and gain of function in disease pathogenesis. The extensive body of molecular, cellular, animal, and human neuropathological studies is conflicted, but the predominance of evidence favors gain of toxicity as the main pathogenic mechanism for C9orf72 repeat expansions. Alterations in several downstream cellular functions, such as nucleocytoplasmic transport and autophagy, are implicated. Exciting progress has also been made in therapy development targeting this mutation, such as by antisense oligonucleotide therapies targeting sense transcripts and small molecules targeting nucleocytoplasmic transport, and these are now in phase 1 clinical trials.
| S-EPMC6985338 | biostudies-literature
Project description:Large expansions of a non-coding GGGGCC-repeat in the first intron of the C9orf72 gene are a common cause of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). G-rich sequences have a propensity for forming highly stable quadruplex structures in both RNA and DNA termed G-quadruplexes. G-quadruplexes have been shown to be involved in a range of processes including telomere stability and RNA transcription, splicing, translation and transport. Here we show using NMR and CD spectroscopy that the C9orf72 hexanucleotide expansion can form a stable G-quadruplex, which has profound implications for disease mechanism in ALS and FTD.
| S-EPMC3527825 | biostudies-other
Project description:Since the discovery of the chromosome 9 open reading frame 72 (C9orf72) repeat expansion mutation in 2011 as the most common genetic abnormality in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease) and frontotemporal dementia (FTD), progress in understanding the signaling pathways related to this mutation can only be described as intriguing. Two major theories have been suggested-(i) loss of function or haploinsufficiency and (ii) toxic gain of function from either C9orf72 repeat RNA or dipeptide repeat proteins (DPRs) generated from repeat-associated non-ATG (RAN) translation. Each theory has provided various signaling pathways that potentially participate in the disease progression. Dysregulation of the immune system, particularly glial cell dysfunction (mainly microglia and astrocytes), is demonstrated to play a pivotal role in both loss and gain of function theories of C9orf72 pathogenesis. In this review, we discuss the pathogenic roles of glial cells in C9orf72 ALS/FTD as evidenced by pre-clinical and clinical studies showing the presence of gliosis in C9orf72 ALS/FTD, pathologic hallmarks in glial cells, including TAR DNA-binding protein 43 (TDP-43) and p62 aggregates, and toxicity of C9orf72 glial cells. A better understanding of these pathways can provide new insights into the development of therapies targeting glial cell abnormalities in C9orf72 ALS/FTD.
| S-EPMC7912327 | biostudies-literature
Project description:Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) patients with the C9orf72 mutation show predominantly cytoplasmic aggregates of poly-GR and poly-PR proteins that are acutely toxic in various model systems. To identify the molecular mediators of neurotoxicity of poly-GR/PR, we analyzed their interactomes in primary neurons. GFP-(GR)149 and (PR)175-GFP preferentially interacted with RNA-binding proteins, including stress granule-associated and nucleolar proteins, as well as ribosomes. Overexpression of the poly-GR/PR interactors Staufen 1/2 (STAU1/2) and YBX1 led to cytoplasmic aggregation of poly-GR/PR into large stress granule-like inclusions, while the poly-GR/PR interactor nucleophosmin (NPM1) recruited poly-GR into the nucleolus. In addition, poly-PR expression reduced ribosome levels and translation, which is consistent with the widespread reduction of synaptic proteins detected by proteomics. Surprisingly, only GFP-(GR)53, but not GFP-(GR)149, localized to the nucleolus and reduced ribosome levels and translation in neurons, suggesting impaired ribosome biogenesis is driving the acute toxicity commonly observed in vitro. In C9orf72 patient brains, we detected co-aggregation of poly-GR/PR inclusions with ribosomes, but not stress granules. Partial sequestration of ribosomes may chronically impair protein synthesis and contribute to C9orf72 ALS/FTD pathogenesis.
2018-06-27 | PXD008691 | Pride
Project description:Human homologue of yeast UV excision repair protein Rad23b (HR23B) inclusions are found in a number of neurodegenerative diseases, including frontotemporal dementia (FTD), Huntington's disease (HD), spinocerebellar ataxia type 3 and 7 (SCA3/7), fragile X associated tremor/ataxia syndrome (FXTAS) and Parkinson's disease (PD). Here, we describe HR23B pathology in C9ORF72 linked FTD and amyotrophic lateral sclerosis (ALS) cases. HR23B presented in neuropils, intranuclear inclusions and cytoplasmic and perinuclear inclusions and was predominantly found in cortices (frontal, temporal and motor), spinal cord and hippocampal dentate gyrus. HR23B co-localized with poly-GA-, pTDP-43- and p62-positive inclusions in frontal cortex and in hippocampal dentate gyrus, the latter showing higher co-localization percentages. HR23B binding partners XPC, 20S and ataxin-3, which are involved in nucleotide excision repair (NER) and the ubiquitin-proteasome system (UPS), did not show an aberrant distribution. However, C9ORF72 fibroblasts were more sensitive for UV-C damage than healthy control fibroblasts, even though all factors involved in NER localized normally to DNA damage and the efficiency of DNA repair was not reduced. HR23Bs other binding partner NGly1/PNGase, involved in ER-associated degradation (ERAD) of misfolded proteins, was not expressed in the majority of neurons in C9FTD/ALS brain sections compared to non-demented controls. Our results suggest a difference in HR23B aggregation and co-localization pattern with DPRs, pTDP-43 and p62 between different brain areas from C9FTD/ALS cases. We hypothesize that HR23B may play a role in C9ORF72 pathogenesis, possibly by aberrant ERAD functioning.
| S-EPMC6416930 | biostudies-literature