Altered apoptotic responses in neurons lacking RhoB GTPase

Abstract

Caspase 3 activation has been linked to the acute neurotoxic effects of central nervous system damage, as in traumatic brain injury or cerebral ischaemia, and also to the early events leading to long-term neurodegeneration, as in Alzheimer’s disease. However, the precise mechanisms activating caspase 3 in neuronal injury are unclear. RhoB is a member of the Rho GTPase family that is dramatically induced by cerebral ischaemia or neurotrauma, both in preclinical models and clinically. In the current study, we tested the hypothesis that RhoB might directly modulate caspase 3 activity and apoptotic or necrotic responses in neurons. Over-expression of RhoB in the NG108-15 neuronal cell line or in cultured corticohippocampal neurons elevated caspase 3 activity without inducing overt toxicity. Cultured corticohippocampal neurons from RhoB knockout mice did not show any differences in sensitivity to a necrotic stimulus – acute calcium ionophore exposure – compared with neurons from wild-type mice. However, corticohippocampal neurons lacking RhoB exhibited a reduction in the degree of DNA fragmentation and caspase 3 activation induced by the apoptotic agent staurosporine, in parallel with increased neuronal survival. Staurosporine induction of caspase 9 activity was also suppressed. RhoB knockout mice showed reduced basal levels of caspase 3 activity in the adult brain. These data directly implicate neuronal RhoB in caspase 3 activation and the initial stages of programmed cell death, and suggest that RhoB may represent an attractive target for therapeutic intervention in conditions involving elevated caspase 3 activity in the central nervous system.

Neuronal Apoptosis Induced by Selective Inhibition of Rac GTPase versus Global Suppression of Rho Family GTPases Is Mediated by Alterations in Distinct Mitogen-activated Protein Kinase Signaling Cascades

“…Moreover, the downstream effector of Rac, PAK, has been shown to regulate the activation of Rho through GEFs in a variety of cell types (27). Consistent with this idea, Rho has been demonstrated to sensitize corticohippocampal neurons to cell death (28), and inhibition of the Rho effector Rho kinase exerts a neuroprotective FIGURE 6. NSC23766 treatment in CGNs deactivates p90Rsk and Akt leading to increased expression, dephosphorylation, and mitochondrial localization of the proapoptotic BH3-only protein Bad.…”

Cytoprotective effect of the small GTPase RhoB expressed upon treatment of fibroblasts with the Ras‐glucosylating Clostridium sordellii lethal toxin

“…Alternatively, RhoB‐dependent regulation of caspases may involve the effector protein mDia1 [58]. Finally, altered apoptotic responses including changed expression and activation of several caspases have been described in neurons lacking RhoB [59].…”

Rho family GTPases: key players in neuronal development, neuronal survival, and neurodegeneration

“…Furthermore, brain-derived neurotrophic factor protected cortical neurons from phenylalanine-induced apoptosis by suppressing Rho activation ( Zhang et al, 2010 ). Finally, corticohippocampal neurons deficient in RhoB are resistant to staurosporine-induced apoptosis ( Barberan et al, 2011 ). Collectively, these data indicate that aberrant activation of RhoA and/or RhoB may contribute to neuronal apoptosis in a variety of in vitro models of neurodegeneration.…”