Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Zhang, Yong Jie; Gendron, Tania F.; Ebbert, Mark T. W.; Garrett, Aliesha; Yue, Mei; Jansen-West, Karen; Zhang, Xu; Prudencio, Mercedes; Chew, Jeannie; Cook, Casey; Daughrity, Lillian M.; Tong, Jimei; Song, Yuping; Pickles, Sarah; Castanedes‐Casey, Monica; Kurti, Aishe; Rademakers, Rosa; Oskarsson, Björn; Dickson, Dennis W.; Hu, Wenqian; Gitler, Aaron D.; Fryer, John Denis; Petrucelli, Leonard

doi:10.1038/s41591-018-0071-1

Cited by 262 publications

(319 citation statements)

References 45 publications

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“…As positive controls, transfection of polyGA, polyPG, and polyGR cloned downstream of canonical ATG start codons embedded in consensus Kozak sequences (gccATGg) resulted in higher DPR protein expression (Figs EV1C and EV2C) and consequently in higher neuronal cell toxicities, especially for polyGR ( Fig 3A). These results are similar to the toxicity reported for DPR proteins driven by artificial ATG start codons and where polyGR are more toxic than polyGA or polyGP (May et al, 2014;Mizielinska et al, 2014;Yamakawa et al, 2015;Lopez-Gonzalez et al, 2016Schludi et al, 2017;Zhang et al, 2018;Choi et al, 2019). DPR proteins form protein aggregates that are degraded by autophagy (Cristofani et al, 2018).…”

Section: Decreased Expression Of C9orf72 Synergizes Dpr Protein Toxicitysupporting

confidence: 86%

“…Indeed, we found that DPR proteins expressed under their natural sequences caused only limited toxicity, which is consistent with their limited expression. Mutation of their near‐cognate codons into AUG canonical start codons enhanced both DPR protein expression and toxicity, especially for the polyGR DPR protein, as consistently reported in various recent studies (Lopez‐Gonzalez et al , , ; Zhang et al , ; Choi et al , ). Conversely, deletions of these DPR initiation codons abolished neuronal cell death, suggesting that expanded repeats cause little toxicity at the RNA level and that RAN translation initiating within the repeats is not sufficiently efficient to drive toxicity, at least with the limited number of repeats used in the present study.…”

Section: Discussionsupporting

confidence: 70%

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Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

et al. 2020

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Expansion of G4C2 repeats within the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Such repeats lead to decreased expression of the autophagy regulator C9ORF72 protein. Furthermore, sense and antisense repeats are translated into toxic dipeptide repeat (DPR) proteins. It is unclear how these repeats are translated, and in which way their translation and the reduced expression of C9ORF72 modulate repeat toxicity. Here, we found that sense and antisense repeats are translated upon initiation at canonical AUG or near‐cognate start codons, resulting in polyGA‐, polyPG‐, and to a lesser degree polyGR‐DPR proteins. However, accumulation of these proteins is prevented by autophagy. Importantly, reduced C9ORF72 levels lead to suboptimal autophagy, thereby impairing clearance of DPR proteins and causing their toxic accumulation, ultimately resulting in neuronal cell death. Of clinical importance, pharmacological compounds activating autophagy can prevent neuronal cell death caused by DPR proteins accumulation. These results suggest the existence of a double‐hit pathogenic mechanism in ALS/FTD, whereby reduced expression of C9ORF72 synergizes with DPR protein accumulation and toxicity.

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Section: Decreased Expression Of C9orf72 Synergizes Dpr Protein Toxicitysupporting

confidence: 86%

Section: Discussionsupporting

confidence: 70%

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

et al. 2020

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“…GA expression resulted in a small increase in insoluble phosphorylated TDP-43 in one study [92], and rare inclusions in another [93]. The expression of GFP-(GR) 100 using adenovirus-mediated delivery into neonatal mouse brain results in motor deficits and a progressive reduction in associative memory, associated with rare TDP-43 but no poly(GR) inclusions [95]. Surprisingly, although there is evidence for the association of poly(GR) with nucleolar stress, nucleocytoplasmic transport dysfunction and nuclear membrane integrity in cell models and patient tissue [86,[96][97][98][99], no evidence for these pathways was observed in this study.…”

Section: C9orf72mentioning

confidence: 97%

Review: Modelling the pathology and behaviour of frontotemporal dementia

Solomon

Mitchell

Salcher-Konrad

et al. 2019

Neuropathology Appl Neurobio

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Frontotemporal dementia (FTD) encompasses a collection of clinically and pathologically diverse neurological disorders. Clinical features of behavioural and language dysfunction are associated with neurodegeneration, predominantly of frontal and temporal cortices. Over the past decade, there have been significant advances in the understanding of the genetic aetiology and neuropathology of FTD which have led to the creation of various disease models to investigate the molecular pathways that contribute to disease pathogenesis. The generation of in vivo models of FTD involves either targeting genes with known disease‐causative mutations such as GRN and C9orf72 or genes encoding proteins that form the inclusions that characterize the disease pathologically, such as TDP‐43 and FUS. This review provides a comprehensive summary of the different in vivo model systems used to understand pathomechanisms in FTD, with a focus on disease models which reproduce aspects of the wide‐ranging behavioural phenotypes seen in people with FTD. We discuss the emerging disease pathways that have emerged from these in vivo models and how this has shaped our understanding of disease mechanisms underpinning FTD. We also discuss the challenges of modelling the complex clinical symptoms shown by people with FTD, the confounding overlap with features of motor neuron disease, and the drive to make models more disease‐relevant. In summary, in vivo models can replicate many pathological and behavioural aspects of clinical FTD, but robust and thorough investigations utilizing shared features and variability between disease models will improve the disease‐relevance of findings and thus better inform therapeutic development.

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“…Most neuronal DPR aggregates occur as compact round or stellate cytoplasmic inclusions. Diffusely DPR-stained neurons are rare, ~4% of poly-GR positive cells in one study (frontal cortex); these authors speculated, based on in vitro data, that diffuse DPR staining represents a transitional state preceding compact inclusion formation [172]. …”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

“…Like RNA foci, poly-GA inclusions co-localize with, and may sequester, various proteins including Drosha, Unc119, and HR23B in neurons, often leading to protein mislocalization [88, 110, 124, 173]. Moreover, diffuse and aggregated cytoplasmic poly-GR was shown to colocalize with ribosomal proteins S6 and L21 and translation initiation factor eIF3η in frontal cortex from 3 patients with C9orf72 -FTD/ALS [172]. A similar study also reported that poly-GR, and to a lesser extent poly-PR, co-aggregate with STAU2 and several ribosomal proteins including S6, S25, L19, and L36A [54].…”

Section: Clinical and Anatomical Features Of C9orf72-ftd/alsmentioning

confidence: 99%

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

et al. 2018

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What are the most important and treatable pathogenic mechanisms in C9orf72-FTD/ALS? Model-based efforts to address this question are forging ahead at a blistering pace, often with conflicting results. But what does the human neuropathological literature reveal? Here, we provide a critical review of the human studies to date, seeking to highlight key gaps or uncertainties in our knowledge. First, we engage the C9orf72-specific mechanisms, including C9orf72 haploinsufficiency, repeat RNA foci, and dipeptide repeat protein inclusions. We then turn to some of the most prominent C9orf72-associated features, such as TDP-43 loss-of-function, TDP-43 aggregation, and nuclear transport defects. Finally, we review potential disease-modifying epigenetic and genetic factors and the natural history of the disease across the lifespan. Throughout, we emphasize the importance of anatomical precision when studying how candidate mechanisms relate to neuronal, regional, and behavioral findings. We further highlight methodological approaches that may help address lingering knowledge gaps and uncertainties, as well as other logical next steps for the field. We conclude that anatomically oriented human neuropathological studies have a critical role to play in guiding this fast-moving field toward effective new therapies.

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Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis

Cited by 262 publications

References 45 publications

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

Reduced autophagy upon C9ORF72 loss synergizes with dipeptide repeat protein toxicity in G4C2 repeat expansion disorders

Review: Modelling the pathology and behaviour of frontotemporal dementia

C9orf72-FTD/ALS pathogenesis: evidence from human neuropathological studies

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