Department of Cell Biology
Aging; Animals; Brain; Cerebellum; Cerebral Cortex; Corpus Callosum; Cyclin-Dependent Kinase 5; Cyclin-Dependent Kinases; Gene Expression; Hippocampus; Mice; Mice, Knockout; Mice, Transgenic; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Phenotype; Phosphopyruvate Hydratase; Phosphorylation; Signal Transduction
Cyclin-dependent kinase 5 (Cdk5) is activated on binding of activator proteins p35 and p39. A N-terminally truncated p35, termed p25, is generated through cleavage by the Ca(2+)-dependent protease calpain after induction of ischemia in rat brain. p25 has been shown to accumulate in brains of patients with Alzheimer's disease and may contribute to A-beta peptide-mediated toxicity. Studies from transfected neurons as well as p35 and p25 transgenic mice have indicated that Cdk5, when activated by p25, gains some toxic function compared with p35/Cdk5. It remains unclear, however, whether p25/Cdk5 signaling additionally channels into pathways usually used by p35/Cdk5 and whether p25 is associated with a loss of p35 function. To clarify these issues, we have generated p25-transgenic mice in a p35-null background. We find that low levels of p25 during development induce a partial rescue of the p35-/- phenotype in several brain regions analyzed, including a rescue of cell positioning of a subset of neurons in the neocortex. In accordance with the partial rescue of brain anatomy, phosphorylation of the Cdk5 substrate mouse disabled 1 is partially restored during development. Besides this, p25/Cdk5 fails to phosphorylate other substrates that are normally phosphorylated by p35/Cdk5. Our results show that p25 can substitute for p35/Cdk5 under certain circumstances during development. In addition, they suggest that p25 may have lost some functions of p35.
J Neurosci. 2003 Apr 1;23(7):2769-78. Link to article on publisher's website
The Journal of neuroscience : the official journal of the Society for Neuroscience
Patzke, Holger; Maddineni, Upendra; Ayala, Ramses; Morabito, Maria A.; Volker, Janet; Dikkes, Pieter; Ahlijanian, Michael K.; and Tsai, Li-Huei, "Partial rescue of the p35-/- brain phenotype by low expression of a neuronal-specific enolase p25 transgene" (2003). Morabito Lab Publications. 3.