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Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice

Overview of attention for article published in Acta Neuropathologica Communications, March 2017
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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 (81st percentile)
  • Above-average Attention Score compared to outputs of the same age and source (63rd percentile)

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1 news outlet
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2 X users
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2 Facebook pages

Citations

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73 Dimensions

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104 Mendeley
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Title
Age-dependent dopamine transporter dysfunction and Serine129 phospho-α-synuclein overload in G2019S LRRK2 mice
Published in
Acta Neuropathologica Communications, March 2017
DOI 10.1186/s40478-017-0426-8
Pubmed ID
Authors

Francesco Longo, Daniela Mercatelli, Salvatore Novello, Ludovico Arcuri, Alberto Brugnoli, Fabrizio Vincenzi, Isabella Russo, Giulia Berti, Omar S. Mabrouk, Robert T. Kennedy, Derya R. Shimshek, Katia Varani, Luigi Bubacco, Elisa Greggio, Michele Morari

Abstract

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common genetic cause of Parkinson's disease. Here, we investigated whether the G2019S LRRK2 mutation causes morphological and/or functional changes at nigro-striatal dopamine neurons. Density of striatal dopaminergic terminals, nigral cell counts, tyrosine hydroxylase protein levels as well as exocytotic dopamine release measured in striatal synaptosomes, or striatal extracellular dopamine levels monitored by in vivo microdialysis were similar between ≥12-month-old G2019S knock-in mice and wild-type controls. In vivo striatal dopamine release was insensitive to the LRRK2 inhibitor Nov-LRRK2-11, and was elevated by the membrane dopamine transporter blocker GBR-12783. However, G2019S knock-in mice showed a blunted neurochemical and motor activation response to GBR-12783 compared to wild-type controls. Western blot and dopamine uptake analysis revealed an increase in dopamine transporter levels and activity in the striatum of 12-month-old G2019S KI mice. This phenotype correlated with a reduction in vesicular monoamine transporter 2 levels and an enhancement of vesicular dopamine uptake, which was consistent with greater resistance to reserpine-induced hypolocomotion. These changes were not observed in 3-month-old mice. Finally, Western blot analysis revealed no genotype difference in striatal levels of endogenous α-synuclein or α-synuclein bound to DOPAL (a toxic metabolite of dopamine). However, Serine129-phosphorylated α-synuclein levels were higher in 12-month-old G2019S knock-in mice. Immunohistochemistry confirmed this finding, also showing no genotype difference in 3-month-old mice. We conclude that the G2019S mutation causes progressive dysfunctions of dopamine transporters, along with Serine129-phosphorylated α-synuclein overload, at striatal dopaminergic terminals, which are not associated with dopamine homeostasis dysregulation or neuron loss but might contribute to intrinsic dopaminergic terminal vulnerability. We propose G2019S knock-in mice as a presymptomatic Parkinson's disease model, useful to investigate the pathogenic interaction among genetics, aging, and internal or environmental factors leading to the disease.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 104 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
Unknown 104 100%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 24 23%
Researcher 21 20%
Student > Master 12 12%
Student > Doctoral Student 8 8%
Student > Bachelor 6 6%
Other 8 8%
Unknown 25 24%
Readers by discipline Count As %
Neuroscience 23 22%
Biochemistry, Genetics and Molecular Biology 11 11%
Agricultural and Biological Sciences 11 11%
Medicine and Dentistry 8 8%
Chemistry 4 4%
Other 11 11%
Unknown 36 35%
Attention Score in Context

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 07 April 2017.
All research outputs
#2,900,681
of 22,959,818 outputs
Outputs from Acta Neuropathologica Communications
#563
of 1,390 outputs
Outputs of similar age
#55,989
of 307,966 outputs
Outputs of similar age from Acta Neuropathologica Communications
#7
of 19 outputs
Altmetric has tracked 22,959,818 research outputs across all sources so far. Compared to these this one has done well and is in the 87th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,390 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 12.8. This one has gotten more attention than average, scoring higher than 57% 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 307,966 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 81% of its contemporaries.
We're also able to compare this research output to 19 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 63% of its contemporaries.