Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

Schludi, Martin H.; Becker, Lore; Garrett, Lillian; Gendron, Tania F.; Zhou, Qihui; Schreiber, Franziska; Popper, Bastian; Dimou, Leda; Strom, Tim M.; Winkelmann, Juliane; Thaden, Anne von; Rentzsch, Kristin; May, Stephanie; Michaelsen, Meike; Schwenk, Benjamin M.; Tan, Jia; Schöser, Benedikt; Dieterich, Marianne; Petrucelli, Leonard; Hölter, Sabine M.; Wurst, Wolfgang; Fuchs, Helmut; Gailus‐Durner, Valérie; Angelis, Martin Hrabě de; Klopstock, Thomas; Arzberger, Thomas; Edbauer, Dieter

doi:10.1007/s00401-017-1711-0

Cited by 108 publications

(133 citation statements)

References 40 publications

(69 reference statements)

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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%

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%

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

et al. 2020

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“…To investigate DPR-only toxicity, models have been generated where individual DPRs are expressed. When overexpressed, polypeptides of the arginine-rich DPRs glycine-arginine (GR) and proline-arginine (PR) have the greatest potential to induce neurotoxicity in Drosophila, C. elegans and zebrafish [66,67,80,81,[83][84][85][86][87][88], but polypeptides of glycine-alanine (GA) also cause toxicity in Drosophila, zebrafish, chick embryo and mouse models [67,80,[89][90][91][92][93].The expression of 50 or 69 GA repeats via adenovirus-mediated delivery into neonatal mouse brain or zygote injection for (mostly) neuronal expression of 149 GA repeats induce development of primarily motor phenotypes [92][93][94]. However, memory deficits and increased anxiety were also identified in the (GA) 50 model [93].…”

Section: C9orf72mentioning

confidence: 99%

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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“…Poly-GA expression leads to toxicity in heterologous cells, primary neuron cultures and mice (Jovicic et al, 2015; May et al, 2014; Schludi et al, 2017; Yamakawa et al, 2015; Zhang et al, 2016; Zhang et al, 2014). Similar to other toxic aggregating proteins (Olzscha et al, 2011; Park et al, 2013), poly-GA aggregates sequester critical cellular factors including Unc119 and multiple UPS components (May et al, 2014; Zhang et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

Guo

Lehmer

Martínez-Sánchez

et al. 2018

Cell

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340

317

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Summary Protein aggregation and dysfunction of the ubiquitin-proteasome system are hallmarks of many neurodegenerative diseases. Here we address the elusive link between these phenomena employing cryo-electron tomography to dissect the molecular architecture of protein aggregates within intact neurons at high resolution. We focus on the poly-Gly-Ala (GA) aggregates resulting from aberrant translation of an expanded GGGGCC repeat in C9orf72, the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. We find that poly-GA aggregates consist of densely packed twisted ribbons that recruit numerous 26S proteasome complexes, while other macromolecules are largely excluded. Proximity to poly-GA ribbons stabilizes a transient substrate-processing conformation of the 26S proteasome, suggesting stalled degradation. Thus, poly-GA aggregates may compromise neuronal proteostasis by driving the accumulation and functional impairment of a large fraction of cellular proteasomes.

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Spinal poly-GA inclusions in a C9orf72 mouse model trigger motor deficits and inflammation without neuron loss

Cited by 108 publications

References 40 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

In Situ Structure of Neuronal C9orf72 Poly-GA Aggregates Reveals Proteasome Recruitment

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