A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Taylor, J. Paul

doi:10.1073/pnas.1621085114

Cited by 6 publications

(7 citation statements)

References 27 publications

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“…Given that DHX36 is a helicase that resolves G4 structures, we hypothesized that DHX36 might facilitate the transcription of C9-repeat RNA. To test this, we performed an in vitro transcription assay with a plasmid containing 70 G 4 C 2 repeats (pCR8-(G 4 C 2 ) 70 ) driven by a T7 RNA polymerase reporter (27). We incubated the plasmid with T7 polymerase in the presence and absence of rDHX36.…”

Section: Dhx36 Directly Binds C9-repeat G4 Dna In Vitromentioning

confidence: 99%

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The RNA helicase DHX36–G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat–associated translation

Tseng

Sandwith

Green

et al. 2021

Journal of Biological Chemistry

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Section: Dhx36 Directly Binds C9-repeat G4 Dna In Vitromentioning

confidence: 99%

“…RAN translation from G 4 C 2 -repeat RNA (C9RAN) produces dipeptide repeat proteins (DPRs) that aggregate in proteinaceous inclusions. C9RAN DPRs cause proteotoxic stress and disrupt nucleocytoplasmic transport (13,26,27).…”

mentioning

confidence: 99%

The RNA helicase DHX36–G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat–associated translation

Tseng

Sandwith

Green

et al. 2021

Journal of Biological Chemistry

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“…Although patients with C9 ALS-FTD show a modest reduction in C9ORF72 expression that may contribute to disease progression, the disease is most likely driven by a toxic gain of function. At the source of this gain of function are repeat-containing transcripts of C9ORF72 that accumulate in affected neurons and perhaps other cells in the brain and spinal cord (Taylor, 2017), although the specific pathogenic mechanism has not been precisely defined. Limited evidence suggests that these repeat-containing transcripts form RNA foci that sequester and deplete RNA-binding proteins.…”

Section: The Emergence Of Nucleocytoplasmic Transport Defects In C9 Amentioning

confidence: 99%

Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

Kim

Taylor

2017

Neuron

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235

192

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Summary Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease characterized by degeneration of upper and lower motor neurons in the brain and spinal cord. The hallmark pathological feature in most cases of ALS is nuclear depletion and cytoplasmic accumulation of the protein TDP-43 in degenerating neurons. Consistent with this pattern of intracellular protein redistribution, impaired nucleocytoplasmic trafficking has emerged as a mechanism contributing to ALS pathology. Dysfunction in nucleocytoplasmic transport is also an emerging theme in physiological aging and other related neurodegenerative diseases, such as Huntington’s and Alzheimer’s diseases. Here we review transport through the nuclear pore complex, pointing out vulnerabilities that may underlie ALS and potentially contribute to this and other age-related neurodegenerative diseases.

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“…2016). Recent studies have presented strong evidence that expression of dipeptide repeats contribute to C9-ALS by disruption of nucleocytoplasmic transport (reviewed in Taylor 2017), suggesting that the contribution of RNA toxicity due to protein sequestration is not a singular mechanism.…”

Section: Role Of Long Noncoding Rnas In Diseasementioning

confidence: 99%

Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions

Morriss

Cooper

2017

Hum Genet

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An emerging class of long noncoding RNAs (lncRNAs) function as decoy molecules that bind and sequester proteins thereby inhibiting their normal functions. Titration of proteins by lncRNAs has wide-ranging effects affecting nearly all steps in gene expression. While decoy lncRNAs play a role in normal physiology, RNAs expressed from alleles containing nucleotide repeat expansions can be pathogenic due to protein sequestration resulting in disruption of normal functions. This review focuses on commonalities between decoy lncRNAs that regulate gene expression by competitive inhibition of protein function through sequestration and specific examples of nucleotide repeat expansion disorders mediated by toxic RNA that sequesters RNA binding proteins and impedes their normal functions. Understanding how noncoding RNAs compete with various RNA and DNA molecules for binding of regulatory proteins will provide insight into how similar mechanisms contribute to disease pathogenesis.

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A PR plug for the nuclear pore in amyotrophic lateral sclerosis

Cited by 6 publications

References 27 publications

The RNA helicase DHX36–G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat–associated translation

The RNA helicase DHX36–G4R1 modulates C9orf72 GGGGCC hexanucleotide repeat–associated translation

Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases

Protein sequestration as a normal function of long noncoding RNAs and a pathogenic mechanism of RNAs containing nucleotide repeat expansions

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