Activation of mitogen-activated protein kinase cascade and phosphorylation of cytoskeletal proteins after neurone-specific activation of p21ras. I. Mitogen-activated protein kinase cascade.
Alterations in the phosphorylation state of the microtubule-associated protein tau have been associated with the pathogenesis of neurofibrillary degeneration as well as with a neuroprotective action against apoptotic cell death. Mitogen-activated protein kinases (MAPK) phosphorylate tau protein in vitro but the pathophysiological significance of this tau phosphorylation and 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 phosphorylation, 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 phosphorylation and the neuronal cytoskeleton. We took advantage of transgenic mice with neurone-specific expression of activated ras protein (p21H-ras(Val12)). The expression of the transgene in these animals is forced to a subset of neurones by the use of the synapsin I promoter. Activity of B-raf was elevated by 37%, while activity of MAPK (ERK1/ERK2) was increased by 25% associated with a subcellular redistribution from the cytoplasmic to the nuclear compartment. Kinases downstream of MAPK such as p90rsk and glycogen synthase kinase 3beta were only marginally affected. Activity of p70S6 kinase 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.
Holzer
M
M
Paul Flechsig Institute of Brain Research, Department of Neuroanatomy, University of Leipzig, Germany. holm@medizin.uni-leipzig.de
Gärtner
U
U
Klinz
F J
FJ
Narz
F
F
Heumann
R
R
Arendt
T
T
D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology*
D003598:Cytoskeletal Proteins; D020928:Mitogen-Activated Protein Kinases; D010744:Phosphoric Monoester Hydrolases; D016283:Proto-Oncogene Proteins p21(ras)