RhoA/ROCK Regulates Prion Pathogenesis by Controlling Connexin 43 Activity

• Published in: International journal of molecular sciences 2020-02, Vol.21 (4), p.1255
• Main Authors: Kim, Hee-Jun, Kim, Mo-Jong, Mostafa, Mohd Najib, Park, Jeong-Ho, Choi, Hong-Seok, Kim, Yong-Sun, Choi, Eun-Kyoung
• Format: Article
• Language: English
• Subjects: cx43; neuronal cell death; p190rhogap; prion diseases; rhoa; rock
• ISSN: 1422-0067; 1422-0067
• DOI: 10.3390/ijms21041255

Scrapie infection, which converts cellular prion protein (PrP ) into the pathological and infectious isoform (PrP ), leads to neuronal cell death, glial cell activation and PrP accumulation. Previous studies reported that PrP regulates RhoA/Rho-associated kinase (ROCK) signaling and that connexin 43 (Cx43) expression is upregulated in and prion-infected models. However, whether there is a link between RhoA/ROCK and Cx43 in prion disease pathogenesis is uncertain. Here, we investigated the role of RhoA/ROCK signaling and Cx43 in prion diseases using and in models. Scrapie infection induced RhoA activation, accompanied by increased phosphorylation of LIM kinase 1/2 (LIMK1/2) at Thr508/Thr505 and cofilin at Ser3 and reduced phosphorylation of RhoA at Ser188 in hippocampal neuronal cells and brains of mice. Scrapie infection-induced RhoA activation also resulted in PrP accumulation followed by a reduction in the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). Interestingly, scrapie infection significantly enhanced the interaction between RhoA and Cx43. Moreover, RhoA and Cx43 colocalization was more visible in both the membrane and cytoplasm of scrapie-infected hippocampal neuronal cells than in controls. Finally, RhoA and ROCK inhibition reduced PrP accumulation and the RhoA/Cx43 interaction, leading to decreased Cx43 hemichannel activity in scrapie-infected hippocampal neuronal cells. These findings suggest that RhoA/ROCK regulates Cx43 activity, which may have an important role in the pathogenesis of prion disease.