casein-kinase-ii and Neurodegenerative-Diseases

The conventional term 'casein kinase' (CK) denotes three classes of kinases - CK1, CK2 and Golgi-CK (G-CK)/Fam20C (family with sequence similarity 20, member C) - sharing the ability to phoshorylate casein in vitro, but otherwise unrelated to each other. All CKs have been reported to be implicated in human diseases, and reviews individually dealing with the druggability of CK1 and CK2 are available. Our aim is to provide a comparative analysis of the three classes of CKs as therapeutic targets.. CK2 is the CK for which implication in neoplasia is best documented, with the survival of cancer cells often relying on its overexpression. An ample variety of cell-permeable CK2 inhibitors have been developed, with a couple of these now in clinical trials. Isoform-specific CK1 inhibitors that are expected to play a beneficial role in oncology and neurodegeneration have been also developed. In contrast, the pathogenic potential of G-CK/Fam20C is caused by its loss of function. Activators of Fam20C, notably sphingolipids and their analogs, may prove beneficial in this respect.. Optimization of CK2 and CK1 inhibitors will prove useful to develop new therapeutic strategies for treating cancer and neurodegenerative disorders, while the design of potent activators of G-CK/Fam20C will provide a new tool in the fields of bio-mineralization and hypophosphatemic diseases.

Topics: Animals; Casein Kinase I; Casein Kinase II; Drug Design; Extracellular Matrix Proteins; Humans; Hypophosphatemia; Molecular Targeted Therapy; Neoplasms; Neurodegenerative Diseases; Protein Kinase Inhibitors

Following the discovery of the human kinome, protein kinases have become the second most important group of drug targets as they can be modulated by small ligand molecules. Moreover, orally active protein kinase inhibitors have recently reached the market and there are many more in clinical trials. The lack of treatments for neurodegenerative diseases has increased human and financial efforts in the search for new therapeutic targets that could provide new effective drug candidates. The importance of kinases in the molecular pathway of neuronal survival is under study, but different key pathways have been described. New roles for the old casein kinases 1 and 2, currently known as protein kinases CK1 and CK2, have recently been discovered in the molecular pathology of different neurodegenerative disorders, such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis. The search for specific inhibitors of these enzymes has become an important challenge for the treatment of these devastating diseases. The role of these two kinases in the molecular pathology of different neurodegenerative diseases together with different chemical families that are able to more or less specifically inhibit CK1 and CK2 are discussed in this review.

Topics: Alzheimer Disease; Amyotrophic Lateral Sclerosis; Animals; Binding, Competitive; Casein Kinase I; Casein Kinase II; Drug Design; Enzyme Inhibitors; Humans; Inhibitory Concentration 50; Mice; Neurodegenerative Diseases; Parkinson Disease; Phosphorylation; Rats

In Lewy body diseases and multiple system atrophy, alpha-synuclein is hyperphosphorylated at Ser129, suggesting a role in pathogenesis. Here, we report purification of the protein kinase in rat brain that phosphorylates Ser129 and its identification as casein kinase-2 (CK2). We show that most of the activity can be inhibited by heparin, an inhibitor of CK2. Phosphorylated Ser129 was detected in primary cultured neurons and inhibited by CK2 inhibitors. In some cases of Lewy body disease, CK2-like immunoreactivity was recovered in the sarkosyl-insoluble fraction, which was enriched in phosphorylated alpha-synuclein. Taken together, these findings suggest that CK2 may be involved in the hyperphosphorylation of alpha-synuclein in alpha-synucleinopathies.

Topics: Alanine; alpha-Synuclein; Animals; Brain; Casein Kinase II; Epitopes; Heparin; Humans; Mutation; Neurodegenerative Diseases; Phosphoserine; Rats; Tissue Culture Techniques

The complex of Cdk5 and its neuronal activator p35 is a proline-directed Ser/Thr kinase that plays an important role in various neuronal functions. Deregulation of the Cdk5 enzymatic activity was found to associate with a number of neurodegenerative diseases. To search for regulatory factors of Cdk5-p35 in the brain, we developed biochemical affinity isolation using a recombinant protein comprising the N-terminal 149 amino acids of p35. The catalytic alpha-subunit of protein kinase CK2 (formerly known as casein kinase 2) was identified by mass spectrometry from the isolation. The association of CK2 with p35 and Cdk5 was demonstrated, and the CK2-binding sites were delineated in p35. Furthermore, CK2 displayed strong inhibition toward the Cdk5 activation by p35. The Cdk5 inhibition is dissociated from the kinase function of CK2 because the kinase-dead mutant of CK2 displayed the similar Cdk5 inhibitory activity as the wild-type enzyme. Further characterization showed that CK2 blocks the complex formation of Cdk5 and p35. Together, these findings suggest that CK2 acts as an inhibitor of Cdk5 in the brain.

Topics: Animals; Binding Sites; Casein Kinase II; Catalytic Domain; Cell Line, Tumor; Chromatography; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Gene Expression Regulation, Enzymologic; Glutathione Transferase; Humans; Immunoprecipitation; Mass Spectrometry; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurons; Phosphorylation; Plasmids; Proline; Protein Binding; Protein Structure, Tertiary; Rats; Recombinant Proteins; RNA Interference; RNA, Small Interfering; Transfection