The pathophysiology of proximal neurofilamentous giant axonal swellings: implications for the pathogenesis of amyotrophic lateral sclerosis.

Neurofilamentous giant axonal swellings are observed in a number of human disorders, although they can manifest at different locations (i.e. proximal or distal) along the axon. Recent advances in understanding the pathogenesis of these changes has resulted from correlations of ultrastructural changes with abnormalities in the axonal transport of neurofilament proteins in experimental models produced by toxic chemicals. Using single, high doses of either acrylamide or 2,5-hexanedione, a reduction in neurofilament transport has been shown in the rat sciatic nerve. In contrast to the distal axonal swellings observed upon repeated exposures to these agents, modest proximal axonal swellings containing increased neurofilament content are found following high dose exposures. Thus, regardless of the location of swelling production, a defect in slow transport appears to underlie swelling formation. beta,beta'-Iminodipropionitrile (IDPN) produces proximal neurofilamentous giant axonal swellings which are indistinguishable from those observed in some patients with amyotrophic lateral sclerosis (ALS). Although not a model for ALS, IDPN provides a means to study the functional consequences of proximal giant axonal swellings. Intracellular recordings from IDPN-intoxicated cats reveal a number of abnormalities which may have electrophysiological counterparts in ALS, suggesting that the swellings may be important in the expression of the disease. Although axonal degeneration is rarely observed in the cat, perikaryal recordings reveal a number of alterations which are strikingly similar to those obtained from chromatolytic motor neurons following nerve transection. A perturbation of "trophic" signals from the periphery may be involved in the generation of axotomy-like changes in IDPN-intoxicated cats.