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PHOSPHORYLATION AND SEQUENCE DEPENDENCY OF NEUROFILAMENT PROTEIN OXIDATIVE MODIFICATION IN ALZHEIMER DISEASE

Liu, Quan
http://rave.ohiolink.edu/etdc/view?acc_num=case1102024839

Abstract Details

2005, Doctor of Philosophy, Case Western Reserve University, Pathology.
Protein adducts of the lipid peroxidation product 4-hydroxy-2-nonenal (HNE) are prominent features of oxidative damage in neuronal cell bodies in Alzheimer disease (AD). Such adducts are also seen in axons of normal as well as diseased individuals. These HNE adducts are constant throughout the axons and the aging process of humans, mice, and rats, indicating that HNE adduction is physiological and regulated from birth to senility. In axons, HNE is primarily adducted to the neurofilament heavy subunit (NFH) and the neurofilament medium subunit (NFM), and limited to lysine residues. Interestingly, we found that phosphorylation is essential since formation and removal of HNE adducts are controlled by the NFH/M phosphorylation state. Studies using immunochemistry, synthetic peptides, mass spectrometry and chemical stabilization of HNE adducts, demonstrated that XKSPX, the most repeated sequences in NFH/M, are the major component in neurons highly susceptible to phosphorylation regulated aldehyde adduction. To our knowledge, this is the first study to directly show phosphorylation can regulate NFH-HNE levels in axons and the multiple KSP repeats are the critical motifs which preserve the phosphorylation-dependent regulation. This study provides the new evidence that indicates signal transduction could modulate oxidative modification in brain through activation of kinases and phosphatases.
George Perry (Advisor)
246 p.
alzheimer disease; phosphorylation; HNE; KSP; neurofilament; Tau; peptide; oxidative modification; free radical

Recommended Citations

Citations

  • Liu, Q. (2005). PHOSPHORYLATION AND SEQUENCE DEPENDENCY OF NEUROFILAMENT PROTEIN OXIDATIVE MODIFICATION IN ALZHEIMER DISEASE [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1102024839

    APA Style (7th edition)

  • Liu, Quan. PHOSPHORYLATION AND SEQUENCE DEPENDENCY OF NEUROFILAMENT PROTEIN OXIDATIVE MODIFICATION IN ALZHEIMER DISEASE. 2005. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1102024839.

    MLA Style (8th edition)

  • Liu, Quan. "PHOSPHORYLATION AND SEQUENCE DEPENDENCY OF NEUROFILAMENT PROTEIN OXIDATIVE MODIFICATION IN ALZHEIMER DISEASE." Doctoral dissertation, Case Western Reserve University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=case1102024839

    Chicago Manual of Style (17th edition)

case1102024839
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© 2004, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.