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Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis

Overview of attention for article published in Molecular Neurodegeneration, June 2018
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (87th percentile)
  • High Attention Score compared to outputs of the same age and source (94th percentile)

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Title
Protective paraspeckle hyper-assembly downstream of TDP-43 loss of function in amyotrophic lateral sclerosis
Published in
Molecular Neurodegeneration, June 2018
DOI 10.1186/s13024-018-0263-7
Pubmed ID
Authors

Tatyana A. Shelkovnikova, Michail S. Kukharsky, Haiyan An, Pasquale Dimasi, Svetlana Alexeeva, Osman Shabir, Paul R. Heath, Vladimir L. Buchman

Abstract

Paraspeckles are subnuclear bodies assembled on a long non-coding RNA (lncRNA) NEAT1. Their enhanced formation in spinal neurons of sporadic amyotrophic lateral sclerosis (ALS) patients has been reported but underlying mechanisms are unknown. The majority of ALS cases are characterized by TDP-43 proteinopathy. In current study we aimed to establish whether and how TDP-43 pathology may augment paraspeckle assembly. Paraspeckle formation in human samples was analysed by RNA-FISH and laser capture microdissection followed by qRT-PCR. Mechanistic studies were performed in stable cell lines, mouse primary neurons and human embryonic stem cell-derived neurons. Loss and gain of function for TDP-43 and other microRNA pathway factors were modelled by siRNA-mediated knockdown and protein overexpression. We show that de novo paraspeckle assembly in spinal neurons and glial cells is a hallmark of both sporadic and familial ALS with TDP-43 pathology. Mechanistically, loss of TDP-43 but not its cytoplasmic accumulation or aggregation augments paraspeckle assembly in cultured cells. TDP-43 is a component of the microRNA machinery, and recently, paraspeckles have been shown to regulate pri-miRNA processing. Consistently, downregulation of core protein components of the miRNA pathway also promotes paraspeckle assembly. In addition, depletion of these proteins or TDP-43 results in accumulation of endogenous dsRNA and activation of type I interferon response which also stimulates paraspeckle formation. We demonstrate that human or mouse neurons in vitro lack paraspeckles, but a synthetic dsRNA is able to trigger their de novo formation. Finally, paraspeckles are protective in cells with compromised microRNA/dsRNA metabolism, and their assembly can be promoted by a small-molecule microRNA enhancer. Our study establishes possible mechanisms behind paraspeckle hyper-assembly in ALS and suggests their utility as therapeutic targets in ALS and other diseases with abnormal metabolism of microRNA and dsRNA.

X Demographics

X Demographics

The data shown below were collected from the profiles of 15 X users who shared this research output. Click here to find out more about how the information was compiled.
Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 113 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 113 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 25 22%
Student > Master 21 19%
Researcher 13 12%
Student > Bachelor 6 5%
Student > Postgraduate 5 4%
Other 12 11%
Unknown 31 27%
Readers by discipline Count As %
Biochemistry, Genetics and Molecular Biology 34 30%
Agricultural and Biological Sciences 16 14%
Neuroscience 15 13%
Medicine and Dentistry 6 5%
Unspecified 3 3%
Other 9 8%
Unknown 30 27%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 18. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 01 December 2019.
All research outputs
#1,792,333
of 23,316,003 outputs
Outputs from Molecular Neurodegeneration
#168
of 864 outputs
Outputs of similar age
#40,283
of 330,994 outputs
Outputs of similar age from Molecular Neurodegeneration
#2
of 18 outputs
Altmetric has tracked 23,316,003 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 92nd percentile: it's in the top 10% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 864 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 14.5. This one has done well, scoring higher than 80% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 330,994 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 87% of its contemporaries.
We're also able to compare this research output to 18 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 94% of its contemporaries.