A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration

Solomon, Daniel A.; Stepto, Alan; Au, Wing Hei; Adachi, Yoshiyuki; Diaper, Danielle C.; Hall, Richard L.; Rekhi, Anjeet; Boudi, Adel; Tziortzouda, Paraskevi; Lee, Youn‐Bok; Smith, Bradley N.; Bridi, Jéssika Cristina; Spinelli, Greta; Dearlove, Jonah; Humphrey, Dickon M.; Gallo, Jean‐Marc; Troakes, Claire; Fanto, Manolis; Soller, Matthias; Rogelj, Boris; Parsons, Richard B.; Shaw, Christopher E.; Hortobágyi, Tibor; Hirth, Frank

doi:10.1093/brain/awy241

Cited by 81 publications

(111 citation statements)

References 57 publications

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“…Among the DPR proteins, poly‐GA has been most robustly linked to TDP‐43 aggregation in vitro , although the mechanism is still unknown (Schludi et al , ; Khosravi et al , ; Lee et al , ; Nonaka et al , ; Solomon et al , ). We co‐expressed all DPRs with the aggregation‐prone CTF of TDP‐43 tagged with RFP.…”

Section: Resultsmentioning

confidence: 99%

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

et al. 2020

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The C9orf72 repeat expansion causes amyotrophic lateral sclerosis and frontotemporal dementia, but the poor correlation between C9orf72-specific pathology and TDP-43 pathology linked to neurodegeneration hinders targeted therapeutic development.Here, we addressed the role of the aggregating dipeptide repeat proteins resulting from unconventional translation of the repeat in all reading frames. Poly-GA promoted cytoplasmic mislocalization and aggregation of TDP-43 non-cell-autonomously, and anti-GA antibodies ameliorated TDP-43 mislocalization in both donor and receiver cells. Cell-to-cell transmission of poly-GA inhibited proteasome function in neighboring cells. Importantly, proteasome inhibition led to the accumulation of TDP-43 ubiquitinated within the nuclear localization signal (NLS) at lysine 95. Mutagenesis of this ubiquitination site completely blocked poly-GA-dependent mislocalization of TDP-43. Boosting proteasome function with rolipram reduced both poly-GA and TDP-43 aggregation. Our data from cell lines, primary neurons, transgenic mice, and patient tissue suggest that poly-GA promotes TDP-43 aggregation by inhibiting the proteasome cell-autonomously and non-cell-autonomously, which can be prevented by inhibiting poly-GA transmission with antibodies or boosting proteasome activity with rolipram.

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Section: Resultsmentioning

confidence: 99%

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

et al. 2020

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“…Although described in C9orf72 ALS iPSC-derived neurons [170], colocalization of RanGAP1 puncta with RNA foci has yet to be reported in patient tissues. A recent study observed nuclear depletion and cytosolic accumulation of KPNA4, a member of karyopherin-α family involved in the nuclear import pathway, in the frontal cortex of sporadic and C9orf72 -FTD/ALS, with the phenotype being more pronounced in patients with the C9orf72 expansion [134]. This nuclear depletion was observed in neurons with and without sense-encoded DPR or phosphorylated TDP-43 inclusions.…”

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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“…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. However, in Drosophila, expression of both (GR) 64 and (GA) 64 could cause the mislocalization of its homologues of TDP-43 and karyopherins 2 and 4 [100].…”

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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A feedback loop between dipeptide-repeat protein, TDP-43 and karyopherin-α mediates C9orf72-related neurodegeneration

Cited by 81 publications

References 57 publications

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

Cell‐to‐cell transmission of C9orf72 poly‐(Gly‐Ala) triggers key features of ALS / FTD

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

Review: Modelling the pathology and behaviour of frontotemporal dementia

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