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Casein kinase 1 isoforms in degenerative disorders

Kannanayakal, Theresa Joseph
http://rave.ohiolink.edu/etdc/view?acc_num=osu1094264800

Abstract Details

2004, Doctor of Philosophy, Ohio State University, Biophysics.
Casein Kinase 1 (CK1) enzyme is one of the largest family of Serine/Threonine protein kinases. CK1 has a wide distribution spanning many eukaryotic families. In cells, its kinase activity has been found in various sub-cellular compartments enabling it to phosphorylate many proteins involved in cellular maintenance and disease pathogenesis. Tau is one such substrate whose hyperphosphorylation results in degeneration of neurons in Alzheimer’s disease (AD). AD is a slow neuroprogessive disorder which is histopathologically characterized by Granulovacuolar degeneration bodies (GVBs) and intraneuronal accumulation of tau in Neurofibrillary Tangles (NFTs). The level of CK1 isoforms, CK1α , CK1δ and CK1ε has been shown to be elevated in AD. Previous studies of the correlation of CK1δ with lesions had demonstrated its importance in tau hyperphosphorylation. Hence we investigated distribution of CK1α and CK1ε with the lesions to understand if they would play a role in tau hyperphosphorylation similar to CK1δ. The kinase results were also compared with lesion correlation studies of peptidyl cis/trans prolyl isomerase (Pin1) and caspase-3. Our results showed that among the enzymes investigated, CK1 isoforms have the greatest extent of colocalization with the lesions. We have also investigated the distribution of CK1α with different stages of NFTs that follow AD progression. It was observed that CK1α follows AD progression, establishing the importance of CK1 isoforms in AD. Correlation of CK1 isoforms with tau pathology led us to investigate the presence of the isoforms in a muscle degenerative disorder, Inclusion Body Myositis (IBM) containing tau inclusions. CK1α was found in the tau inclusions of IBM, demonstrating the importance of CK1 isoforms in degenerative disorders in general. Since CK1 is established in both maintenance of the cell and pathogenesis of degenerative diseases, we investigated the regulation and protein substrate recognition of the kinase domain of the enzymes. Using structure and sequence comparison with other conserved protein kinases, we identified and mutated the essential residues involved in regulation and protein substrate recognition. Examination of the mutants with kinase assay revealed that T166 is important for regulation while R183, K222, K229 are important for protein substrate recognition. Thus, these various studies establish the importance of the CK1 family in degenerative disorders.
Jeff Kuret (Advisor)
150 p.
Alzheimer's Disease; Inclusion Body Myositis; Neurodegenerative disorders; Casein Kinase 1; Casein Kinase 1 alpha; Casein Kinase 1 delta; Casein Kinase 1 epsilon; Casein Kinase 1 mutants; Casein Kinase 1 isoforms; Kinase Activity; Kinase Assay

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Citations

  • Kannanayakal, T. J. (2004). Casein kinase 1 isoforms in degenerative disorders [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1094264800

    APA Style (7th edition)

  • Kannanayakal, Theresa. Casein kinase 1 isoforms in degenerative disorders. 2004. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1094264800.

    MLA Style (8th edition)

  • Kannanayakal, Theresa. "Casein kinase 1 isoforms in degenerative disorders." Doctoral dissertation, Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1094264800

    Chicago Manual of Style (17th edition)

osu1094264800
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© 2004, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.