casein-kinase-ii and Amyotrophic-Lateral-Sclerosis

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

We have previously reported that inositol hexakisphosphate kinase (InsP

Topics: Aged; Aged, 80 and over; Amyotrophic Lateral Sclerosis; Anterior Horn Cells; Autopsy; Casein Kinase II; Cell Death; Cell Nucleus; Cytoplasm; Female; Gene Expression Regulation; HSP90 Heat-Shock Proteins; Humans; Immunohistochemistry; Male; Middle Aged; Phosphorylation; Phosphotransferases (Phosphate Group Acceptor); Pleckstrin Homology Domains; Protein Domains; Proto-Oncogene Proteins c-akt; Spinal Cord

Several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) are characterized by inclusion bodies formed by TDP-43 (TDP). We established cell and transgenic Drosophila models expressing TDP carboxyl terminal fragment (ND251 and ND207), which developed aggregates recapitulating important features of TDP inclusions in ALS/FTLD-U, including hyperphosphorylation at previously reported serine(403,404,409,410) residues, polyubiquitination and colocalization with optineurin. These models were used to address the pathogenic role of hyperphosphorylation in ALS/FTLD-U. We demonstrated that hyperphosphorylation and ubiquitination occurred temporally later than aggregation in cells. Expression of CK2α which phosphorylated TDP decreased the aggregation propensity of ND251 or ND207; this effect could be blocked by CK2 inhibitor DMAT. Mutation of serines(379,403,404,409,410) to alanines (S5A) to eliminate phosphorylation increased the aggregation propensity and number of aggregates of TDP, but mutation to aspartic acids (S5D) or glutamic acids (S5E) to simulate hyperphosphorylation had the opposite effect. Functionally, ND251 or ND207 aggregates decreased the number of neurites of Neuro2a cells induced by retinoic acid or number of cells by MTT assay. S5A mutation aggravated, but S5E mutation alleviated these cytotoxic effects of aggregates. Finally, ND251 or ND251S5A developed aggregates in neurons, and salivary gland of transgenic Drosophila, but ND251S5E did not. Taken together, our data indicate that hyperphosphorylation may represent a compensatory defense mechanism to stop or prevent pathogenic TDP from aggregation. Therefore, enhancement of phosphorylation may serve as an effective therapeutic strategy against ALS/FTLD-U.

Topics: Amyotrophic Lateral Sclerosis; Animals; Animals, Genetically Modified; Benzimidazoles; Casein Kinase II; Cell Line; Cell Proliferation; DNA-Binding Proteins; Drosophila; Humans; Immunoblotting; Phosphorylation; Polyubiquitin; Protein Binding; Protein Multimerization; Reverse Transcriptase Polymerase Chain Reaction; Salivary Glands