Regulation of RhoA activity by the cellular prion protein
The cellular prion protein (PrP ) 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 essen...
Saved in:
Published in | Cell death & disease Vol. 8; no. 3; p. e2668 |
---|---|
Main Authors | , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Springer Nature B.V
16.03.2017
Nature Publishing Group |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | The cellular prion protein (PrP
) 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 PrP
using both in vitro and in vivo models and found that overexpression of PrP
significantly induced RhoA inactivation and RhoA phosphorylation in hippocampal neuronal cells and in the brains of transgenic mice. Using siRNA-mediated depletion of endogenous PrP
and overexpression of disease-associated mutants of PrP
, we confirmed that PrP
induced RhoA inactivation, which accompanied RhoA phosphorylation but reduced the phosphorylation levels of LIM kinase (LIMK), leading to cofilin activation. In addition, PrP
colocalized with RhoA, and the overexpression of PrP
significantly increased neurite outgrowth in nerve growth factor-treated PC12 cells through RhoA inactivation. However, the disease-associated mutants of PrP
decreased neurite outgrowth compared with wild-type PrP
. Moreover, inhibition of Rho-associated kinase (ROCK) substantially facilitated neurite outgrowth in NGF-treated PC12 cells, similar to the effect induced by PrP
. Interestingly, we found that the induction of RhoA inactivation occurred through the interaction of PrP
with RhoA and that PrP
enhanced the interaction between RhoA and p190RhoGAP (a GTPase-activating protein). These findings suggest that the interactions of PrP
with RhoA and p190RhoGAP contribute to neurite outgrowth by controlling RhoA inactivation and RhoA-mediated signaling and that disease-associated mutations of PrP
impair RhoA inactivation, which in turn leads to prion-related neurodegeneration. |
---|---|
Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 2041-4889 2041-4889 |
DOI: | 10.1038/cddis.2017.37 |