The proposed studies reflect my longstanding interest in the role of cytoskeletal proteins (in particular, tubulin and the neurofilament proteins) in the mechanism of axonal regeneration and in the pathogenesis of neurodegenerative diseases. Tubulin, one of the major proteins of the cytoskeleton, appears to play an essential role in the outgrowth (elongation) of regenerating axons. Preliminary studies indicate that significant quantities of unassembled tubulin are transported in the axon. The first goal of the proposed studies is to confirm this finding and to examine the hypothesis that the polymerization of this (unassembled) tubulin at or near the growing axon tip is a necessary step in the outgrowth process. The second goal is to test the hypothesis that acrylamide impairs outgrowth by interfering with this polymerization. The state of polymerization of transported tubulin, labeled by the intraspinal injection of [35S] methionine, will be assessed using the method of Pipeleers et al. [1977]. If the proposed studies demonstrate that the polymerization of tubulin is necessary for outgrowth, then future studies will examine the regulation of this process, since factors blocking it could, potentially, be responsible for the lack of outgrowth in the mammalian central nervous system. Neurofilamentous pathology is a prominent feature of several neurodegenerative disorders. Using the toxin Beta, Beta'-iminodipropionitrile (IDPN), we demonstrated that neurofilamentous axonal pathology similar to that observed in the human disease amyotrophic lateral sclerosis results from a selective impairment in neurofilament transport. Recent evidence suggests that the axonal transport of neurofilaments plays an important role in regulating the caliber of healthy axons. The third goal of the proposed studies is to confirm this observation using the proximal stump of the regenerating axon as a model system. Morphometric observations will be correlated with axonal transport studies designed to extend our previous observation that the axonal transport of neurofilaments is selectively reduced in regenerating neurons. In addition to providing new information concerning the control of caliber in healthy axons, these studies should provide new insights into the pathogenesis of diseases in which alterations in axonal caliber are a prominent feature.
| Hoffman, P N; Pollock, S C; Striph, G G (1993) Altered gene expression after optic nerve transection: reduced neurofilament expression as a general response to axonal injury. Exp Neurol 119:32-6 |
| Hoffman, P N (1989) Expression of GAP-43, a rapidly transported growth-associated protein, and class II beta tubulin, a slowly transported cytoskeletal protein, are coordinated in regenerating neurons. J Neurosci 9:893-7 |
| Hoffman, P N; Cleveland, D W (1988) Neurofilament and tubulin expression recapitulates the developmental program during axonal regeneration: induction of a specific beta-tubulin isotype. Proc Natl Acad Sci U S A 85:4530-3 |
| Hoffman, P N (1988) Distinct roles of neurofilament and tubulin gene expression in axonal growth. Ciba Found Symp 138:192-204 |
| Hoffman, P N; Griffin, J W; Gold, B G et al. (1985) Slowing of neurofilament transport and the radial growth of developing nerve fibers. J Neurosci 5:2920-9 |
