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Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation

Overview of attention for article published in Acta Neuropathologica Communications, September 2018
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  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (72nd percentile)

Mentioned by

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11 tweeters

Citations

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8 Dimensions

Readers on

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19 Mendeley
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Title
Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation
Published in
Acta Neuropathologica Communications, September 2018
DOI 10.1186/s40478-018-0600-7
Pubmed ID
Authors

Maggie M. K. Wong, Stephanie D. Hoekstra, Jane Vowles, Lauren M. Watson, Geraint Fuller, Andrea H. Németh, Sally A. Cowley, Olaf Ansorge, Kevin Talbot, Esther B. E. Becker

Abstract

Spinocerebellar ataxia type 14 (SCA14) is a subtype of the autosomal dominant cerebellar ataxias that is characterized by slowly progressive cerebellar dysfunction and neurodegeneration. SCA14 is caused by mutations in the PRKCG gene, encoding protein kinase C gamma (PKCγ). Despite the identification of 40 distinct disease-causing mutations in PRKCG, the pathological mechanisms underlying SCA14 remain poorly understood. Here we report the molecular neuropathology of SCA14 in post-mortem cerebellum and in human patient-derived induced pluripotent stem cells (iPSCs) carrying two distinct SCA14 mutations in the C1 domain of PKCγ, H36R and H101Q. We show that endogenous expression of these mutations results in the cytoplasmic mislocalization and aggregation of PKCγ in both patient iPSCs and cerebellum. PKCγ aggregates were not efficiently targeted for degradation. Moreover, mutant PKCγ was found to be hyper-activated, resulting in increased substrate phosphorylation. Together, our findings demonstrate that a combination of both, loss-of-function and gain-of-function mechanisms are likely to underlie the pathogenesis of SCA14, caused by mutations in the C1 domain of PKCγ. Importantly, SCA14 patient iPSCs were found to accurately recapitulate pathological features observed in post-mortem SCA14 cerebellum, underscoring their potential as relevant disease models and their promise as future drug discovery tools.

Twitter Demographics

The data shown below were collected from the profiles of 11 tweeters who shared this research output. Click here to find out more about how the information was compiled.

Mendeley readers

The data shown below were compiled from readership statistics for 19 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 19 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 4 21%
Student > Bachelor 3 16%
Student > Master 3 16%
Student > Doctoral Student 2 11%
Student > Ph. D. Student 2 11%
Other 3 16%
Unknown 2 11%
Readers by discipline Count As %
Agricultural and Biological Sciences 5 26%
Neuroscience 4 21%
Medicine and Dentistry 3 16%
Physics and Astronomy 1 5%
Social Sciences 1 5%
Other 3 16%
Unknown 2 11%

Attention Score in Context

This research output has an Altmetric Attention Score of 7. 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 12 June 2019.
All research outputs
#3,026,385
of 15,922,988 outputs
Outputs from Acta Neuropathologica Communications
#550
of 941 outputs
Outputs of similar age
#75,118
of 278,284 outputs
Outputs of similar age from Acta Neuropathologica Communications
#1
of 1 outputs
Altmetric has tracked 15,922,988 research outputs across all sources so far. Compared to these this one has done well and is in the 80th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 941 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.5. This one is in the 41st percentile – i.e., 41% of its peers scored the same or lower than it.
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 278,284 tracked outputs that were published within six weeks on either side of this one in any source. This one has gotten more attention than average, scoring higher than 72% of its contemporaries.
We're also able to compare this research output to 1 others from the same source and published within six weeks on either side of this one. This one has scored higher than all of them