title: Regulation of RhoA activity by the cellular prion protein.
abstract: The cellular prion protein (PrPC) is a highly conserved glycosylphosphatidylinositol (GPI)-anchored membrane protein that is involved in the signal transduction during the initial phase of neurite outgrowth. The Ras homolog gene family member A (RhoA) is a small GTPase that is known to have an essential role in regulating the development, differentiation, survival, and death of neurons in the central nervous system. Although recent studies have shown the dysregulation of RhoA in a variety of neurodegenerative diseases, the role of RhoA in prion pathogenesis remains unclear. Here, we investigated the regulation of RhoA-mediated signaling by PrPCusing both in vitro and in vivo models and found that overexpression of PrPCsignificantly induced RhoA inactivation and RhoA phosphorylation in hippocampal neuronal cells and in the brains of transgenic mice. Using siRNA-mediated depletion of endogenous PrPCand overexpression of disease-associated mutants of PrPC, we confirmed that PrPCinduced RhoA inactivation, which accompanied RhoA phosphorylation but reduced the phosphorylation levels of LIM kinase (LIMK), leading to cofilin activation. In addition, PrPCcolocalized with RhoA, and the overexpression of PrPCsignificantly increased neurite outgrowth in nerve growth factor-treated PC12 cells through RhoA inactivation. However, the disease-associated mutants of PrPCdecreased neurite outgrowth compared with wild-type PrPC. Moreover, inhibition of Rho-associated kinase (ROCK) substantially facilitated neurite outgrowth in NGF-treated PC12 cells, similar to the effect induced by PrPC. Interestingly, we found that the induction of RhoA inactivation occurred through the interaction of PrPCwith RhoA and that PrPCenhanced the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). These findings suggest that the interactions of PrPCwith RhoA and p190RhoGAP contribute to neurite outgrowth by controlling RhoA inactivation and RhoA-mediated signaling and that disease-associated mutations of PrPCimpair RhoA inactivation, which in turn leads to prion-related neurodegeneration.
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.
authors.forename: Hee-Jun
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.|Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Hong-Seok
authors.initials: HS
authors.lastname: Choi
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.|Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Jeong-Ho
authors.initials: JH
authors.lastname: Park
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.|Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Republic of Korea.
authors.forename: Mo-Jong
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Department of Biology, The University of Texas at San Antonio, San Antonio, TX, USA.
authors.forename: Hyoung-Gon
authors.initials: HG
authors.lastname: Lee
authors.affiliation: Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.|Departments of Neuroscience and Neurology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Robert Bob
authors.initials: RB
authors.lastname: Petersen
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.|Department of Microbiology, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Medicine, Hallym University, Chuncheon, Republic of Korea.
authors.forename: Jae-Bong
authors.initials: JB
authors.lastname: Park
authors.affiliation: Ilsong Institute of Life Science, Hallym University, Anyang, Republic of Korea.|Department of Biomedical Gerontology, Graduate School of Hallym University, Chuncheon, Republic of Korea.
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000502:physiology; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D054461:Lim Kinases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic / Q000378:metabolism; D016501:Neurites / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation / Q000502:physiology; D000072002:Prion Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000502:physiology; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020690:GTPase-Activating Proteins; D000072002:Prion Proteins; D034741:RNA, Small Interfering; D054461:Lim Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein