Neurofilaments (NF), the major cytoskeletal proteins expressed in mature myelinated axons, are intrinsic determinants of axonal diameter (caliber). Maintenance of axonal caliber is important since conduction velocity of nerve action potentials is a function of axonal diameter. NF modulation of axonal caliber appears to be determined not by NF number, per se, but by their phosphorylation state. The mechanisms controlling NF phosphorylation are not understood. However, abnormal phosphorylation and accumulation of NF proteins are features of Alzheimer's disease (AD) and the motor neuron disease amyotrophic lateral sclerosis (ALS). The applicant is studying protein kinases that phosphorylate NF using mouse as a model system. He has identified and characterized a novel 115 kDa NF-associated kinase from mouse brain extracts, which has been named NAK115. NAK115 is expressed in neurons and its activity is down-regulated during myelination induced in culture. A kinase related to NAK115 is found in human brain. In addition to NAK115 two other NF kinases have been discovered. One of these appears to be a novel cdc2-like kinase that is associated with NF in mouse brain. A kinases with similar immunological properties has also been found in humans and is associated with the paired helical filaments that comprise the neurofibrillary tangles of Alzheimer disease. A 35 kDa NF kinase whose activity is up-regulated by myelination has also been discovered. In order to fully understand the regulation NF phosphorylation by these kinases, the applicant proposes to characterize the kinases biochemically, immunologically and at the molecular level. In a consortium study, it will also be determined whether the three NF kinases are associated with NF proteins during axonal transport in nerve fibers. In these studies it will also be determined whether axonal transport of the kinases are impaired to the same extent as the NF proteins after systemic intoxication with IDPN (beta,beta'-iminodipropionitrile), a neurotoxin that selectively blocks NF transport without significantly altering the transport of other cytoskeletal proteins, such as actin or tubulin. Finally, the applicant proposes to study how expression of the NF kinases changes during peripheral nerve injury when the cytoskeleton is restructured. These studies should provide valuable information on the association and transport of kinases with NF proteins, and role of the kinases in modification of NF proteins in neuronal function during normal development, during nerve injury, and in human diseases in which NF are affected.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG011386-07
Application #
6055381
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1992-09-01
Project End
2001-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
7
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Neurology
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Judge, Susan I V; Yeh, Jay Z; Goolsby, James E et al. (2002) Determinants of 4-aminopyridine sensitivity in a human brain kv1.4 k(+) channel: phenylalanine substitutions in leucine heptad repeat region stabilize channel closed state. Mol Pharmacol 61:913-20
Mah, A L; Perry, G; Smith, M A et al. (2000) Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation. J Cell Biol 151:847-62
Janicki, S M; Monteiro, M J (1999) Presenilin overexpression arrests cells in the G1 phase of the cell cycle. Arrest potentiated by the Alzheimer's disease PS2(N141I)mutant. Am J Pathol 155:135-44
Judge, S I; Monteiro, M J; Yeh, J Z et al. (1999) Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel. Brain Res 831:43-54
Stabler, S M; Ostrowski, L L; Janicki, S M et al. (1999) A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein. J Cell Biol 145:1277-92
Starr, R; Attema, B; DeVries, G H et al. (1996) Neurofilament phosphorylation is modulated by myelination. J Neurosci Res 44:328-37
Monteiro, M J; Mical, T I (1996) Resolution of kinase activities during the HeLa cell cycle: identification of kinases with cyclic activities. Exp Cell Res 223:443-51
Starr, R; Hall, F L; Monteiro, M J (1996) A cdc2-like kinase distinct from cdk5 is associated with neurofilaments. J Cell Sci 109 ( Pt 6):1565-73
Xiao, J; Perry, G; Troncoso, J et al. (1996) alpha-calcium-calmodulin-dependent kinase II is associated with paired helical filaments of Alzheimer's disease. J Neuropathol Exp Neurol 55:954-63
Hsu, C; Janicki, S; Monteiro, M J (1995) The first intron of the mouse neurofilament light gene (NF-L) increases gene expression. Brain Res Mol Brain Res 32:241-51

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