PT - JOURNAL ARTICLE AU - Holger Patzke AU - Upendra Maddineni AU - Ramses Ayala AU - Maria Morabito AU - Janet Volker AU - Pieter Dikkes AU - Michael K. Ahlijanian AU - Li-Huei Tsai TI - Partial Rescue of the p35−/− Brain Phenotype by Low Expression of a Neuronal-Specific Enolase p25 Transgene AID - 10.1523/JNEUROSCI.23-07-02769.2003 DP - 2003 Apr 01 TA - The Journal of Neuroscience PG - 2769--2778 VI - 23 IP - 7 4099 - http://www.jneurosci.org/content/23/7/2769.short 4100 - http://www.jneurosci.org/content/23/7/2769.full SO - J. Neurosci.2003 Apr 01; 23 AB - 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 Ca2+-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-β 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.