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Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis

Overview of attention for article published in Journal of Neuroinflammation, March 2016
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About this Attention Score

  • In the top 25% of all research outputs scored by Altmetric
  • Good Attention Score compared to outputs of the same age (79th percentile)
  • Good Attention Score compared to outputs of the same age and source (68th percentile)

Mentioned by

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1 news outlet

Citations

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14 Dimensions

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62 Mendeley
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Title
Reciprocal signals between microglia and neurons regulate α-synuclein secretion by exophagy through a neuronal cJUN-N-terminal kinase-signaling axis
Published in
Journal of Neuroinflammation, March 2016
DOI 10.1186/s12974-016-0519-5
Pubmed ID
Authors

Dan Ploug Christensen, Patrick Ejlerskov, Izabela Rasmussen, Frederik Vilhardt

Abstract

Secretion of proteopathic α-synuclein (α-SNC) species from neurons is a suspected driving force in the propagation of Parkinson's disease (PD). We have previously implicated exophagy, the exocytosis of autophagosomes, as a dominant mechanism of α-SNC secretion in differentiated PC12 or SH-SY5Y nerve cells. Here we have examined the regulation of exophagy associated with different forms of nerve cell stress relevant to PD. We identify cJUN-N-terminal kinase (JNK) activity as pivotal in the secretory fate of autophagosomes containing α-SNC. Pharmacological inhibition or genetic (shRNA) knockdown of JNK2 or JNK3 decreases α-SNC secretion in differentiated PC12 and SH-SY5Y cells, respectively. Conversely, expression of constitutively active mitogen-activated protein kinase kinase 7 (MKK7)-JNK2 and -JNK3 constructs augment secretion. The transcriptional activity of cJUN was not required for the observed effects. We establish a causal relationship between increased α-SNC release by exophagy and JNK activation subsequent to lysosomal fusion deficiency (overexpression of Lewy body-localized protein p25α or bafilomycin A1). JNK activation following neuronal ER or oxidative stress was not correlated with exophagy, but of note, we demonstrate that reciprocal signaling between microglia and neurons modulates α-SNC secretion. NADPH oxidase activity of microglia cell lines was upregulated by direct co-culture with α-SNC-expressing PC12 neurons or by passive transfer of nerve cell-conditioned medium. Conversely, inflammatory factors secreted from activated microglia increased JNK activation and α-SNC secretion several-fold in PC12 cells. While we do not identify these factors, we extend our observations by showing that exposure of neurons in monoculture to TNFα, a classical pro-inflammatory mediator of activated microglia, is sufficient to increase α-SNC secretion in a mechanism dependent on JNK2 or JNK3. In continuation hereof, we show that also IFNβ and TGFβ increase the release of α-SNC from PC12 neurons. We implicate stress kinases of the JNK family in the regulation of exophagy and release of α-SNC following endogenous or exogenous stimulation. In a wider scope, our results imply that microglia not only inflict bystander damage to neurons in late phases of inflammatory brain disease but may also be active mediators of disease propagation.

Mendeley readers

The data shown below were compiled from readership statistics for 62 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 2%
United States 1 2%
Unknown 60 97%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 15 24%
Researcher 14 23%
Student > Bachelor 7 11%
Student > Master 5 8%
Student > Postgraduate 4 6%
Other 11 18%
Unknown 6 10%
Readers by discipline Count As %
Agricultural and Biological Sciences 17 27%
Biochemistry, Genetics and Molecular Biology 12 19%
Neuroscience 11 18%
Medicine and Dentistry 7 11%
Engineering 3 5%
Other 5 8%
Unknown 7 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 11 March 2016.
All research outputs
#998,616
of 7,380,163 outputs
Outputs from Journal of Neuroinflammation
#170
of 953 outputs
Outputs of similar age
#55,047
of 278,102 outputs
Outputs of similar age from Journal of Neuroinflammation
#14
of 57 outputs
Altmetric has tracked 7,380,163 research outputs across all sources so far. Compared to these this one has done well and is in the 85th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 953 research outputs from this source. They receive a mean Attention Score of 4.5. This one has done well, scoring higher than 79% 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 278,102 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 79% of its contemporaries.
We're also able to compare this research output to 57 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 68% of its contemporaries.