Transgenic activation of Ras in neurons promotes hypertrophy and protects from lesion-induced degeneration

Ras is a universal eukaryotic intracellular protein integrating extracellul ar signals from multiple receptor types. To investigate its role in the adu lt central nervous system, constitutively activated V12-Ha-Ras was expresse d selectively in neurons of transgenic mice via a synapsin promoter. Ras-tr ansgene protein expression increased postnatally, reaching a four- to fivef old elevation at day 40 and persisting at this level, thereafter, Neuronal Ras was constitutively active and a corresponding activating phosphorylatio n of mitogen-activated kinase was observed, but there were no changes in th e activity of phosphoinositide 3-kinase, the phosphorylation of its target kinase Akt/PKB, or expression of the anti-apoptotic proteins Bcl-2 or Bcl-X -L. Neuronal Ras activation did not alter the total number of neurons, but induced cell soma hypertrophy, which resulted in a 14.5% increase of total brain volume. Choline acetyltransferase and tyrosine hydroxylase activities were increased, as well as neuropeptide Y expression, Degeneration of moto rneurons was completely prevented after facial nerve lesion in Ras-transgen ic mice. Furthermore, neurotoxin-induced degeneration of dopaminergic subst antia nigra neurons and their striatal projections was greatly attenuated. Thus, the Ras signaling pathway mimics neurotrophic effects and triggers ne uroprotective mechanisms in adult mice, Neuronal Ras activation might becom e a tool to stabilize donor neurons for; neural transplantation and to prot ect neuronal populations in neurodegenerative diseases.