casein-kinase-ii and Memory-Disorders

Data on the nuclear cascade of signal transduction, including protein kinase CK2 (PKCK2), transcription factor HMG14 and chromatin myosin-like proteins, are generalized with regard for the modern understanding of mechanisms of synaptic plasticity. The role of the neurospecific isoform and subunit structure of PKCK2, of the individual subunit autophosphorylation of PKCK2, of phosphorylation of substrate-proteins in the enzyme activity and of conformation transformations of chromatin is examined. Data on changes in the CK2-induced cascade and synaptic plasticity in learning, on age-related amnesia and on cognitive deficits induced by ethanol and chloridine in rat embryos are presented. The prospects for using modulators PKCK2, 4,5-di(N-methylcarbamoyl)-l-alkyl-imidazoles, as potential nootropics are discussed.

Topics: Animals; Casein Kinase II; Cognition Disorders; Memory Disorders; Neuronal Plasticity; Oxidative Phosphorylation; Protein Serine-Threonine Kinases; Rats; Signal Transduction

Casein kinase II (CK2) is a multifunctional serine/threonine protein kinase that is associated with the development of neuritogenesis and synaptic plasticity. The phosphoinositide 3-kinase (PI-3K)/Akt pathway is implicated in long-term memory formation. In addition, serum- and glucocorticoid-inducible kinase 1 (SGK1) is another downstream target of PI-3K signaling that was shown to play an important role in spatial memory formation. Whether CK2 may also affect memory formation and whether CK2 interacts with Akt and SGK1 during this process is unknown. In the present study, we found that water maze training significantly decreased CK2 activity in the rat hippocampal CA1 area but not in the dentate gyrus (DG) area. Transfection of the dominant negative mutant of CK2, CK2alphaA(156), to the CA1 area, but not to the DG area, decreased CK2 activity but enhanced spatial memory formation. Meanwhile, it increased SGK1 phosphorylation at Ser422, decreased Akt phosphorylation at Ser473, and increased cAMP response element-binding protein phosphorylation at Ser133. Transfection of the constitutively active SGK1, SGKS422D, enhanced whereas transfection of the wild-type Akt impaired spatial memory formation. Also, administration of the protein phosphatase 2A inhibitor, fostriecin, reversed the memory-impairing effect of CK2alphaWT. It also reversed the effect of CK2alphaWT in decreasing SGK1 phosphorylation. Akt Ser473 phosphorylation was moderately increased by CK2alphaWT and fostriecin treatment, but AktS473A mutant transfection reversed the memory-impairing effect of CK2alphaWT. These results together suggest that CK2 impairs spatial memory formation through differential cross talk with PI-3 kinase signaling by activation of Akt and inactivation of SGK1 through protein phosphatase 2A.

Topics: Animals; Casein Kinase II; Down-Regulation; Enzyme Activation; Immediate-Early Proteins; Male; Maze Learning; Memory Disorders; Phosphatidylinositol 3-Kinases; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; Receptor Cross-Talk; Signal Transduction; Spatial Behavior

Identifying the genetic factors that contribute to memory and learning is limited by the complexity of brain development and the lack of suitable human models for mild disorders of cognition.. Previously, a disease locus was mapped for a mild type of nonsyndromic mental retardation (IQ between 50 and 70) to a 4.2-MB interval on chromosome 3p25-pter in a large kindred. The genes and transcripts within the candidate region were systematically analyzed for mutations by single-strand polymorphism analysis and DNA sequencing.. A nonsense mutation causing a premature stop codon in a novel gene (cereblon; CRBN) was identified that encodes for an ATP-dependent Lon protease. The predicted protein sequence is highly conserved across species, and it belongs to a family of proteins that selectively degrade short-lived polypeptides and regulate mitochondrial replication and transcription. One member of the Lon-containing protein family is regionally expressed in the human hippocampus, an important neuroanatomic region that is involved in long-term potentiation and learning. The mutation in the CRBN gene described interrupts an N-myristoylation site and eliminates a casein kinase II phosphorylation site at the C terminus.. A gene on chromosome 3p that is associated with mild mental retardation in a large kindred is reported. This finding implicates a role for the ATP-dependent degradation of proteins in memory and learning.

Topics: Adaptor Proteins, Signal Transducing; Amino Acid Sequence; Casein Kinase II; Chromosomes, Human, Pair 3; Codon, Nonsense; Consanguinity; Consensus Sequence; Exons; Female; Founder Effect; Humans; Intellectual Disability; Learning Disabilities; Male; Memory Disorders; Molecular Sequence Data; Myristic Acid; Nerve Tissue Proteins; Pedigree; Peptide Hydrolases; Phenotype; Phosphorylation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Protein Processing, Post-Translational; Sequence Alignment; Sequence Homology, Amino Acid; Ubiquitin-Protein Ligases