Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease

Eftekharzadeh, Bahareh; Daigle, J. Gavin; Kapinos, Larisa E.; Coyne, Alyssa N.; Schiantarelli, Julia; Carlomagno, Yari; Cook, Casey; Miller, Sean; Dujardin, Simon; Amaral, André Cestonaro do; Grima, Jonathan C.; Bennett, Rachel E.; Tepper, Katharina; DeTure, Michael; Vanderburg, Charles; Corjuc, Bianca T.; DeVos, Sarah L.; González, José Emilio Caballero; Chew, Jeannie; Vidensky, Svetlana; Gage, Fred H.; Mertens, Jérôme; Troncoso, Juan C.; Mandelkow, Eckhard; Salvatella, Xavier; Lim, Roderick Y. H.; Petrucelli, Leonard; Wegmann, Susanne; Rothstein, Jeffrey D.; Hyman, Bradley T.

doi:10.1016/j.neuron.2018.12.031

Cited by 84 publications

(122 citation statements)

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“…While the nature for this differential effect is not clear, it could be associated with the biophysical or functional properties of each repeat expansion, its subcellular localization, or even the size of the repeat itself. Nevertheless, these results suggest that impaired N/C trafficking could be broadly implicated in repeat expansion-related toxicity, corroborating recent studies for HD and AD models 24,[28][29][30] .…”

Section: Repeat Expansion Mutations Lead To Proteome Wide Nucleo-cytosupporting

confidence: 89%

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Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Ortega

Daley

Kour

et al. 2019

Preprint

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The most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) is a hexanucleotide repeat expansion in C9orf72 (C9-HRE). While RNA and dipeptide repeats produced by the C9-HRE disrupt nucleocytoplasmic transport, the proteins that become redistributed remain unknown. Here, we utilized subcellular fractionation coupled with tandem mass spectrometry and identified 126 proteins, enriched for protein translation and RNA metabolism pathways, which collectively drive a shift towards a more cytosolic proteome in C9-HRE cells. Amongst these was ETF1, which regulates translation termination and nonsense-mediated decay (NMD). ETF1 accumulates within elaborate nuclear envelope invaginations in patient iPSC-neurons and postmortem tissue and mediates a protective shift from protein translation to NMD-dependent mRNA degradation. Overexpression of ETF1 and the NMD-driver UPF1 ameliorate C9-HRE toxicity in vivo. Our findings provide a resource for proteome-wide nucleocytoplasmic alterations across neurodegenerationassociated repeat expansion mutations and highlight ETF1 and NMD as therapeutic targets in C9orf72-associated ALS/FTD. KEYWORDSAmyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), C9orf72, ETF1, nonsense mediated decay (NMD), UPF1, nucleocytoplasmic proteome, iPSCs, motor neurons. through three non-exclusive mechanisms 5-8 . Several reports have shown that C9orf72 expression is decreased in patients suggesting that haploinsufficiency contributes to pathogenesis 9, 10 . Gain-of-function neurotoxic effects occur through the production of aberrant C9-HRE RNA molecules 11 , as well as through dipeptide repeat proteins (DPRs) translated by a non-ATG dependent mechanism from the HRE 12, 13 . The repeat is bi-directionally transcribed and corresponding RNA sense and antisense molecules are detected by fluorescence in situ hybridization (FISH) as predominantly nuclear RNA foci in patient cells and tissue 11,13,14 . Moreover, five C9-HRE DPRs (GA, GP, GR, PR, PA) have been detected with antigen-specific antibodies in patient samples where they accumulate in cytoplasmic and nuclear aggregates in the frontal and motor cortex as well as the spinal cord 15,16 .While the relative contribution of loss-of-function effects, as well as the dominant source of toxic gain-of-function effects (RNA or DPRs) is still an open-ended question, substantial and converging evidence suggests that the C9-HRE disrupts the balance of proteins that are transported between the nucleus and the cytoplasm. The long C9-RNA that is transcribed from the repeat expansion binds and sequesters RNA-binding proteins in the nucleus 11 . The argininerich GR and PR C9-DPRs bind and sequester a number of proteins with low complexity domains that assemble into membrane-less organelles through liquid-liquid phase separation 17, 18 . These include RNA granules, nucleoli and various components of the nuclear pore complex (NPC). Consequently, a series of groundbreaking genetic studies in C9-HRE Drosophila and yeast mod...

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Section: Repeat Expansion Mutations Lead To Proteome Wide Nucleo-cytosupporting

confidence: 89%

“…The transport of mRNA and proteins between the nucleus and the cytoplasm has emerged as a critical cellular pathway in neurodegenerative diseases 24,28,30,61,62 . Here, we developed an approach to assess how the repeat expansion in C9orf72 impacts the subcellular N/C distribution of proteins.…”

Section: Discussionmentioning

confidence: 99%

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Ortega

Daley

Kour

et al. 2019

Preprint

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“…Recent data suggest that NTRs can also modulate the biophysical state and toxicity of several IDPs related to neurodegenerative diseases [134,[141][142][143][144][145][146]. Moreover, several repeat-proteins that are associated with neurodegenerative diseases are known to disrupt nucleocytoplasmic transport [34,136,142,144,[146][147][148][149]. Altogether, these recent findings suggest that the FG-Nups may be at risk in aging if NTR levels become limiting, or if cells have a larger load of aggregation-prone proteins that may sequester NPC components into aberrant phase-separated states or aggregates.…”

Section: Maintenance Quiescent Muscle Cells Maintain Theirmentioning

confidence: 99%

Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

2020

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The nuclear pore complex (NPC) is the sole gateway to the nuclear interior, and its function is essential to all eukaryotic life. Controlling the functionality of NPCs is a tremendous challenge for cells. Firstly, NPCs are large structures, and their complex assembly does occasionally go awry. Secondly, once assembled, some components of the NPC persist for an extremely long time and, as a result, are susceptible to accumulate damage. Lastly, a significant proportion of the NPC is composed of intrinsically disordered proteins that are prone to aggregation. In this review, we summarize how the quality of NPCs is guarded in young cells and discuss the current knowledge on the fate of NPCs during normal aging in different tissues and organisms. We discuss the extent to which current data supports a hypothesis that NPCs are poorly maintained during aging of nondividing cells, while in dividing cells the main challenge is related to the assembly of new NPCs. Our survey of current knowledge points toward NPC quality control as an important node in aging of both dividing and nondividing cells. Here, the loss of protein homeostasis during aging is central and the NPC appears to both be impacted by, and to drive, this process.

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“…Similarly, increased levels of lamin B1 affects nuclear export in HEK293 cells 16 and reduces nuclear ion channel opening in fibroblasts from autosomal dominant leukodystrophy patients 17 . Furthermore, altered lamin B levels and nucleocytoplasmic transport occur in AD 45 and PD 46 although these alterations have never been linked between them. Altered nucleocytoplasmic mRNA transport has been previously reported in other HD models and has been indirectly associated with nucleoporins sequestration by mhtt inclusions 10,11 .…”

Section: Discussionmentioning

confidence: 99%

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

Alcalà-Vida

Garcia‐Forn

Creus-Muncunill

et al. 2020

Preprint

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Lamins are crucial proteins for nuclear functionality. Here, we provide new evidence showing an involvement of increased lamin B1 levels in the pathophysiology of Huntington's disease (HD), a CAG repeat-associated neurodegenerative disorder. Through fluorescence-activated nuclear suspension imaging we demonstrate that nucleus from striatal medium-sized spiny and CA1 hippocampal neurons display increased lamin B1 levels, in correlation with altered nuclear morphology and nucleocytoplasmic transport disruption. Moreover, ChIP-sequencing analysis shows an alteration of lamin-associated chromatin domains in hippocampal nuclei, which could contribute to transcriptional alterations we determined by RNA sequencing. Supporting lamin B1 alterations as a causal role in mutant-huntingtin mediated neurodegeneration, pharmacological normalization of lamin B1 levels by betulinic acid administration in the R6/1 mouse model of HD restored nuclear homeostasis and prevented motor and cognitive dysfunction. Collectively, our work point out increased lamin B1 levels as a new pathogenic mechanism in HD and provides a novel target for its intervention.Keywords: chromatin accessibility, LAD, R6/1 mouse, nuclear morphology, nuclear permeability of the polyglutamine chain at the amino terminus of the huntingtin (Htt) protein inducing selfassociation and aggregation. Consequently, mutant Htt (mHtt) loses its biological functions and becomes toxic 13 . In HD, medium-sized spiny neurons (MSNs), the GABAergic output projection neurons that account for the vast majority (90-95%) of all striatal neurons, are mainly affected. Although motor symptoms are the most prominent, psychiatric alterations and cognitive decline appear first in HD patients, which become more evident as the disease progresses. Cognitive deficits are related to the dysfunction of the corticostriatal pathway and the hippocampus and, together with motor deficits, have been replicated in most HD mouse models 14 .Molecular mechanisms leading to nuclear lamina alterations in neurons expressing mHtt remain to be elucidated. Previous results from our lab suggested that decreased levels of the pro-apoptotic kinase PKC would lead to an aberrant accumulation of lamin B 15 which, in turn, could have a significant influence in the nuclear lamina structure 16,17 . Therefore, here we sought to deeply characterize the impact of lamin alterations in HD brain at physiological (studying nuclear lamina morphology and nucleo-cytoplasmic transport), transcriptomic (by generating RNA-sequencing (RNA-seq) data) and epigenetic (analyzing lamin chromatin binding and chromatin accessibility) levels by using the R6/1 transgenic mouse model of HD and human post-mortem brain samples. ResultsLamin B levels are increased in a region-specific manner in HD brain. Lamin B1, B2, and A/C protein levels were analyzed in the striatum, cortex and hippocampus of wild-type and R6/1 mice, a transgenic mouse model of HD over-expressing the exon 1 of the human mutant huntingtin 18 , at different ages. Western blot a...

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Tau Protein Disrupts Nucleocytoplasmic Transport in Alzheimer’s Disease

Cited by 84 publications

References 0 publications

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Nucleocytoplasmic Proteomic Analysis Uncovers eRF1 and Nonsense Mediated Decay as Modifiers of ALS C9orf72 Toxicity

Poor old pores—The challenge of making and maintaining nuclear pore complexes in aging

Neuron-specific increase in lamin B1 disrupts nuclear function in Huntington’s disease

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