The neuronal cytoskeleton is intimately involved in maintaining the size and shape of axons and dendrites. The proposed studies examine the transport and organization of neurofilaments within the axonal cytoskeleton. The experiments aim to given new insight into normal developmental processes and into pathological processes which may be pertinent to human disorders such as amyotrophic lateral sclerosis (ALS), spinal muscular atrophies, peripheral neuropathies, and Alzheimer's disease. The first studies concern the mechanisms of radial growth of axons in sciatic nerve during development. Previous studies have shown that neurofilaments occupy most of the volume of large axons, and that neurofilament number and axonal cross-sectional area are closely related throughout development, suggesting that neurofilament delivery is likely to regulate axonal growth. The proposed studies assess the relative contribution of increased neurofilament synthesis and retardation of neurofilament transport along the axon for determining radial growth. The studies also will assess the changes in neurofilament synthesis and transport and correlate them with axonal size during the atrophy caused by axotomy. The post-translational modification of neurofilaments, for example, phosphorylation, will be investigated and correlated with changes in the velocity of neurofilament transport. A different set of studies will examine transport of cytoskeletal proteins in selected CNS pathways, using techniques developed in the PNS. These studies will provide the necessary foundations for examining neurofilament transport in the disorders marked by neurofibrillary degeneration. A third set of studies is stimulated by the observation that material can be obtained from peripheral nerve that is highly enriched in neurofilaments which are organized into large bundles. These studies will investigate molecular interactions are responsible for the interfilament links in such preparations, with the aim of giving insight into the factors controlling interfilament linking in normal and pathologic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Academic/Teacher Award (ATA) (K07)
Project #
5K07NS000983-02
Application #
3078410
Study Section
Neurological Disorders Program Project Review B Committee (NSPB)
Project Start
1985-08-01
Project End
1990-07-31
Budget Start
1986-08-01
Budget End
1987-07-31
Support Year
2
Fiscal Year
1986
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Archer, D R; Watson, D F; Griffin, J W (1994) Phosphorylation-dependent immunoreactivity of neurofilaments and the rate of slow axonal transport in the central and peripheral axons of the rat dorsal root ganglion. J Neurochem 62:1119-25
Watson, D F; Fittro, K P (1993) Transport of cytoskeletal proteins in axons of hippocampal pyramidal cells. Hippocampus 3:539-46
Watson, D F; Fittro, K P; Hoffman, P N et al. (1991) Phosphorylation-related immunoreactivity and the rate of transport of neurofilaments in chronic 2,5-hexanedione intoxication. Brain Res 539:103-9
Watson, D (1991) Regional variation in the abundance of axonal cytoskeletal proteins. J Neurosci Res 30:226-31
Watson, D F; Griffin, J W; Fittro, K P et al. (1989) Phosphorylation-dependent immunoreactivity of neurofilaments increases during axonal maturation and beta,beta'-iminodipropionitrile intoxication. J Neurochem 53:1818-29
Watson, D F; Hoffman, P N; Fittro, K P et al. (1989) Neurofilament and tubulin transport slows along the course of mature motor axons. Brain Res 477:225-32
Griffin, J W; Watson, D F (1988) Axonal transport in neurological disease. Ann Neurol 23:3-13
Watson, D F; Griffin, J W (1987) Vacor neuropathy: ultrastructural and axonal transport studies. J Neuropathol Exp Neurol 46:96-108