Activation of mitogen-activated protein kinase cascade and phosphorylationof cytoskeletal proteins after neurone-specific activation of p21ras. I. Mitogen-activated protein kinase cascade

Alterations in the phosphorylation state of the microtubule-associated prot ein tau have been associated with the pathogenesis of neurofibrillary degen eration as well as with a neuroprotective action against apoptotic cell dea th. Mitogen-activated protein kinases (MAPK) phosphorylate tau protein in v itro but the pathophysiological significance of this tau phosphorylation an d its effects on neuronal viability is far from clear. Moreover, an in vivo model of activation of MAPK, a key candidate for in vivo tau phosphorylati on, is still lacking. The aim of the present study and the accompanying paper was to establish an animal model of stimulated MAPK and to analyse the consequences on tau pho sphorylation and the neuronal cytoskeleton. We took advantage of transgenic mice with neurone-specific expression of activated ras protein (p21H-ras(V a112)). The expression of the transgene in these animals is forced to a sub set of neurones by the use of the synapsin I promoter. Activity of B-raf wa s elevated by 37%, while activity of MAPK (ERK1/ERK2) was increased by 25% associated with a subcellular redistribution from the cytoplasmic to the nu clear compartment. Kinases downstream of MAPK such as p90rsk and glycogen s ynthase kinase 3 beta were only marginally affected. Activity of p70S6 kina se was unaltered. The present model might be useful to study the effects of activation of the MAPK cascade on tau phosphorylation and its cell biological sequelae. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights reserved.