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Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production

Overview of attention for article published in Molecular Neurodegeneration, February 2017
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (85th percentile)
  • Good Attention Score compared to outputs of the same age and source (79th percentile)

Mentioned by

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1 news outlet
twitter
2 tweeters
facebook
3 Facebook pages

Citations

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23 Dimensions

Readers on

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48 Mendeley
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Title
Dynamic presenilin 1 and synaptotagmin 1 interaction modulates exocytosis and amyloid β production
Published in
Molecular Neurodegeneration, February 2017
DOI 10.1186/s13024-017-0159-y
Pubmed ID
Authors

Katarzyna Marta Zoltowska, Masato Maesako, Iryna Lushnikova, Shuko Takeda, Laura J. Keller, Galina Skibo, Bradley T. Hyman, Oksana Berezovska

Abstract

Alzheimer's disease (AD)-linked protein, presenilin 1 (PS1), is present at the synapse, and the knock-out of presenilin in mice leads to synaptic dysfunction. On the other hand, synaptic activity was shown to influence PS1-dependent generation of distinct amyloid β (Aβ) species. However, the precise nature of these regulations remains unclear. The current study reveals novel role of PS1 at the synapse, and deciphers how PS1 and synaptic vesicle-associated protein, synaptotagmin 1 (Syt1) modulate each other functions in neurons via direct activity-triggered interaction. Additionally, the therapeutic potential of fostering PS1-Syt1 binding is investigated as a synapse-specific strategy for AD prevention. PS1-based cell-permeable peptide targeting PS1-Syt1 binding site was designed to inhibit PS1-Syt1 interaction in neurons. PS1 conformation, synaptic vesicle exocytosis and trafficking were assayed by fluorescence lifetime imaging microscopy (FLIM), glutamate release/synaptopHluorin assay, and fluorescence recovery after photobleaching, respectively. Syt1 level and interaction with PS1 in control and sporadic AD brains were determined by immunohistochemistry and FLIM. AAV-mediated delivery of Syt1 into mouse hippocampi was used to investigate the therapeutic potential of strengthening PS1-Syt1 binding in vivo. Statistical significance was determined using two-tailed unpaired Student's t-test, Mann-Whitney's U-test or two-way ANOVA followed by a Bonferroni's post-test. We demonstrate that targeted inhibition of the PS1-Syt1 binding in neurons, without changing the proteins' expression level, triggers "pathogenic" conformational shift of PS1, and consequent increase in the Aβ42/40 ratio. Moreover, our data indicate that PS1, by binding directly to Syt1, regulates synaptic vesicle trafficking and facilitates exocytosis and neurotransmitter release. Analysis of human brain tissue revealed that not only Syt1 levels but also interactions between remaining Syt1 and PS1 are diminished in sporadic AD. On the other hand, overexpression of Syt1 in mouse hippocampi was found to potentiate PS1-Syt1 binding and promote "protective" PS1 conformation. The study reports novel functions of PS1 and Syt1 at the synapse, and demonstrates the importance of PS1-Syt1 binding for exocytosis and safeguarding PS1 conformation. It suggests that reduction in the Syt1 level and PS1-Syt1 interactions in AD brain may present molecular underpinning of the pathogenic PS1 conformation, increased Aβ42/40 ratio, and impaired exocytosis.

Twitter Demographics

The data shown below were collected from the profiles of 2 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 48 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 48 100%

Demographic breakdown

Readers by professional status Count As %
Researcher 12 25%
Student > Ph. D. Student 11 23%
Student > Bachelor 5 10%
Professor 5 10%
Student > Master 3 6%
Other 4 8%
Unknown 8 17%
Readers by discipline Count As %
Neuroscience 12 25%
Biochemistry, Genetics and Molecular Biology 11 23%
Agricultural and Biological Sciences 5 10%
Medicine and Dentistry 4 8%
Environmental Science 1 2%
Other 3 6%
Unknown 12 25%

Attention Score in Context

This research output has an Altmetric Attention Score of 11. 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 14 March 2017.
All research outputs
#1,308,002
of 12,880,924 outputs
Outputs from Molecular Neurodegeneration
#126
of 552 outputs
Outputs of similar age
#49,972
of 344,830 outputs
Outputs of similar age from Molecular Neurodegeneration
#4
of 24 outputs
Altmetric has tracked 12,880,924 research outputs across all sources so far. Compared to these this one has done well and is in the 89th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 552 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.3. This one has done well, scoring higher than 75% 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 344,830 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 85% of its contemporaries.
We're also able to compare this research output to 24 others from the same source and published within six weeks on either side of this one. This one has done well, scoring higher than 79% of its contemporaries.