Synthetic hydrogel mimics of the nuclear pore complex for the study of nucleocytoplasmic transport defects in C9orf72 ALS/FTD

Friedman, Alicia K.; Boeynaems, Steven; Baker, Lane A.

doi:10.1007/s00216-021-03478-2

Cited by 4 publications

(5 citation statements)

References 34 publications

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“…Our analysis of the abundance and localization of the components of the nuclear transport machinery, including NPC components, almost all NTRs, and the components of the Ran gradient, shows that expression of polyGA and polyPR does not induce significant changes. Our data does not support blocking of NPCs, nor does it show prominent colocalization of DPRs with NTRs or the NPC as previously reported 52,87,88 . At the same time, we do find that the expression of both DPRs impact the transport by different NTRs (Crm1, Kap60/Kap95, Kap104, and Kap121/Pse1) to varying degrees and directions.…”

Section: Discussioncontrasting

confidence: 86%

Nuclear transport under stress phenocopies transport defects in models of C9Orf72 ALS

Semmelink

Jafarinia

Wolters

et al. 2022

Preprint

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The nucleus is the hallmark of eukaryotic life and transport to and from the nucleus occurs through the nuclear pore complex (NPC). There is a multitude of data connecting the nuclear transport machinery – i.e. the NPCs and associated nuclear transport factors - to neurodegenerative diseases, but the mechanisms are not well understood. Using Saccharomyces cerevisiae, we systematically studied how the expression of polyPR and polyGA related to C9Orf72 amyotrophic lateral sclerosis impacts the nuclear transport machinery. We measured the abundance and localization of NPC components and transport factors, and assessed the kinetics of import and export by four transport receptors. PolyPR and polyGA cause distinct, and transport receptor dependent effects. We compared the specific changes in transport to those obtained when cells were exposed to different stress situations or mutations. This comparison showed similar patterns of transport defects in cells lacking specific NTRs and cells expressing polyPR. In contrast, polyGA expressing cells bear resemblance to stress conditions where energy maintenance is decreased. The similarity of the patterns of transport deficiencies suggests that polyPR has a direct effect on nuclear transport via NTRs, while polyGA impacts the energy state of the cell and subsequently changes transport.

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Section: Discussioncontrasting

confidence: 86%

Nuclear transport under stress phenocopies transport defects in models of C9Orf72 ALS

Semmelink

Jafarinia

Wolters

et al. 2022

Preprint

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“…R-DPR interactions with FG-domains were also noted in another study, in which GR15 and PR30 were strongly recruited to aFSFG hydrogels (acryloyl-modified phenylalanine-serine-phenylalanine-glycine hydrogels, which are used as a model of FG-interactions), dependent on the FG motifs, whereas GP30 was not (Friedman et al, 2022 ). This study elucidated that the interactions between arginine residues and FG repeats are stable and not transient events, suggesting that in situ , the presence of R-DPRs could reduce the availability of FG-domains to mediate transport across the NPC central channel (Friedman et al, 2022 ). Consistent with this, PR30 pre-treatment completely blocked the entrance of Importin β-1 (which binds FG-repeats) to aFSFG hydrogels and resulted in decreased Importin β-1 mobility (Friedman et al, 2022 ).…”

Section: Abnormalities Of the Npc In C9orf72 -Alsmentioning

confidence: 66%

“…In support of this, cells treated with PR20 showed reduced NPC permeability upon 1,6-hexanediol treatment, which typically dissolves FG-Nup polymers and should increase NPC permeability, thereby supporting that PR20 stabilizes FG-Nups (Shi et al, 2017). R-DPR interactions with FG-domains were also noted in another study, in which GR15 and PR30 were strongly recruited to aFSFG hydrogels (acryloyl-modified phenylalanine-serine-phenylalanine-glycine hydrogels, which are used as a model of FG-interactions), dependent on the FG motifs, whereas GP30 was not (Friedman et al, 2022). This study elucidated that the interactions between arginine residues and FG repeats are stable and not transient events, suggesting that in situ, the presence of R-DPRs could reduce the availability of FG-domains to mediate transport across the NPC central channel (Friedman et al, 2022).…”

Section: Dpr E Ects On the Npcmentioning

confidence: 75%

“…This study elucidated that the interactions between arginine residues and FG repeats are stable and not transient events, suggesting that in situ , the presence of R-DPRs could reduce the availability of FG-domains to mediate transport across the NPC central channel (Friedman et al, 2022 ). Consistent with this, PR30 pre-treatment completely blocked the entrance of Importin β-1 (which binds FG-repeats) to aFSFG hydrogels and resulted in decreased Importin β-1 mobility (Friedman et al, 2022 ). It has also been suggested that R-DPRs could modestly interact with FG-domains both directly and indirectly and that this might be partially selective and dependent on the length of the FG-domain (Hayes et al, 2020 ).…”

Section: Abnormalities Of the Npc In C9orf72 -Alsmentioning

confidence: 96%

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Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

McGoldrick,

Robertson

2023

Front. Cell. Neurosci.

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Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two adult-onset neurodegenerative diseases that are part of a common disease spectrum due to clinical, genetic, and pathological overlap. A prominent genetic factor contributing to both diseases is a hexanucleotide repeat expansion in a non-coding region of the C9orf72 gene. This mutation in C9orf72 leads to nuclear depletion and cytoplasmic aggregation of Tar DNA-RNA binding protein 43 (TDP-43). TDP-43 pathology is characteristic of the majority of ALS cases, irrespective of disease causation, and is present in ~50% of FTD cases. Defects in nucleocytoplasmic transport involving the nuclear pore complex, the Ran-GTPase cycle, and nuclear transport factors have been linked with the mislocalization of TDP-43. Here, we will explore and discuss the implications of these system abnormalities of nucleocytoplasmic transport in C9orf72-ALS/FTD, as well as in other forms of familial and sporadic ALS.

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“…It has also been found that the FG domains of at least 10 Xenopus Nups are capable of forming hydrogels and that Nup98 creates a stricter sieve than other tested Nups ( Labokha et al, 2013 ). Recently, the hydrogel model has been the basis for a study on the effects of dipeptide repeats (DPRs) in the NPC and found that a synthetic hydrogel mimicking FG interactions was disrupted by arginine-rich DPRs, preventing the entry of Impβ ( Friedman et al, 2022 ). These DRPs are associated with C9orf72 repeat expansions, which have been found to be the leading cause of frontotemporal dementia and amyotrophic lateral sclerosis ( Smeyers et al, 2021 ).…”

Section: Models Of the Npc And Nucleocytoplasmic Transportmentioning

confidence: 99%

Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex

Rush,

Jiang,

Tingey

et al. 2023

Front. Cell Dev. Biol.

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The nuclear pore complex (NPC) serves as a pivotal subcellular structure, acting as a gateway that orchestrates nucleocytoplasmic transport through a selectively permeable barrier. Nucleoporins (Nups), particularly those containing phenylalanine–glycine (FG) motifs, play indispensable roles within this barrier. Recent advancements in technology have significantly deepened our understanding of the NPC's architecture and operational intricacies, owing to comprehensive investigations. Nevertheless, the conspicuous presence of intrinsically disordered regions within FG-Nups continues to present a formidable challenge to conventional static characterization techniques. Historically, a multitude of strategies have been employed to unravel the intricate organization and behavior of FG-Nups within the NPC. These endeavors have given rise to multiple models that strive to elucidate the structural layout and functional significance of FG-Nups. Within this exhaustive review, we present a comprehensive overview of these prominent models, underscoring their proposed dynamic and structural attributes, supported by pertinent research. Through a comparative analysis, we endeavor to shed light on the distinct characteristics and contributions inherent in each model. Simultaneously, it remains crucial to acknowledge the scarcity of unequivocal validation for any of these models, as substantiated by empirical evidence.

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Synthetic hydrogel mimics of the nuclear pore complex for the study of nucleocytoplasmic transport defects in C9orf72 ALS/FTD

Cited by 4 publications

References 34 publications

Nuclear transport under stress phenocopies transport defects in models of C9Orf72 ALS

Nuclear transport under stress phenocopies transport defects in models of C9Orf72 ALS

Unraveling the impact of disrupted nucleocytoplasmic transport systems in C9orf72-associated ALS

Unveiling the complexity: assessing models describing the structure and function of the nuclear pore complex

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