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12:57
Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
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RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity
Hee-Jun Kim1, Mo-Jong Kim1,2, Mohd Najib Mostafa1,2
1Ilsong Institute of Life Science, Hallym University, Anyang, Gyeonggi-do 14066, Korea.
International Journal of Molecular Sciences
|February 20, 2020
Summary
Scrapie infection activates RhoA/ROCK signaling, increasing pathological prion protein (PrPSc) accumulation by enhancing the interaction between RhoA and connexin 43 (Cx43). Inhibiting RhoA/ROCK reduces PrPSc and Cx43 activity, suggesting a role in prion disease.
Area of Science:
- Neuroscience
- Molecular Biology
- Cell Biology
Background:
- Scrapie infection converts cellular prion protein (PrPC) to pathological PrPSc, causing neuronal death and PrPSc accumulation.
- PrPC is known to regulate RhoA/Rho-associated kinase (ROCK) signaling.
- Connexin 43 (Cx43) expression increases in prion-infected models, but its link to RhoA/ROCK in prion disease is unclear.
Purpose of the Study:
- To investigate the role of RhoA/ROCK signaling and Cx43 in prion disease pathogenesis.
- To determine if RhoA/ROCK signaling influences Cx43 activity during scrapie infection.
Main Methods:
- Utilized in vitro and in vivo scrapie infection models.
- Analyzed RhoA activation, phosphorylation of downstream targets (LIMK1/2, cofilin), and protein interactions (RhoA/p190RhoGAP, RhoA/Cx43).
- Assessed RhoA and Cx43 colocalization and Cx43 hemichannel activity, with and without RhoA/ROCK inhibition.
Main Results:
- Scrapie infection activated RhoA/ROCK signaling, increased PrPSc accumulation, and reduced RhoA/p190RhoGAP interaction.
- Scrapie infection significantly enhanced RhoA and Cx43 interaction and colocalization in neuronal cells.
- Inhibition of RhoA and ROCK decreased PrPSc accumulation, reduced RhoA/Cx43 interaction, and lowered Cx43 hemichannel activity.
Conclusions:
- RhoA/ROCK signaling pathway is activated during scrapie infection.
- RhoA/ROCK signaling directly regulates Cx43 activity.
- The RhoA/ROCK-Cx43 axis plays a significant role in prion disease pathogenesis, offering potential therapeutic targets.
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