title: 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.
authors.affiliation: Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Barberan
authors.forename: Kara
authors.initials: K
authors.lastname: McNair
authors.forename: Khalil
authors.initials: K
authors.lastname: Iqbal
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Smith
authors.forename: George C
authors.initials: GC
authors.lastname: Prendergast
authors.forename: Trevor W
authors.initials: TW
authors.lastname: Stone
authors.forename: Stuart R
authors.initials: SR
authors.lastname: Cobb
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Morris
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D002478:Cells, Cultured; D053938:DNA Fragmentation; D004789:Enzyme Activation; D017353:Gene Deletion; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D020743:rhoB GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D051028:bcl-2-Associated X Protein; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020743:rhoB GTP-Binding Protein
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