Partial rescue of the p35-/- brain phenotype by low expression of a neuronal-specific enolase p25 transgene.
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.
Patzke
Holger
H
Department of Pathology and Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA.
Maddineni
Upendra
U
Ayala
Ramses
R
Morabito
Maria
M
Volker
Janet
J
Dikkes
Pieter
P
Ahlijanian
Michael K
MK
Tsai
Li-Huei
LH
D000375:Aging; D000818:Animals; D001921:Brain / Q000166:cytology* / Q000196:embryology / Q000201:enzymology / Q000473:pathology; D002531:Cerebellum / Q000166:cytology; D002540:Cerebral Cortex / Q000166:cytology; D003337:Corpus Callosum / Q000166:cytology; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D015870:Gene Expression; D006624:Hippocampus / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000473:pathology; D009474:Neurons / Q000145:classification / Q000201:enzymology; D010641:Phenotype; D010751:Phosphopyruvate Hydratase / Q000235:genetics*; D010766:Phosphorylation; D015398:Signal Transduction
C108298:Cdk5 activator p39; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases; D010751:Phosphopyruvate Hydratase