We have postulated that the toxic neuropathies associated with neurofilament-filled axonal swellings have a common pathogenesis, the covalent crosslinking of neurofilaments during anterograde transport. The newly described -diketone, 3,4-dimethyl-2,5-hexanedione (DMHD), is a more potent analogue of the toxic metabolite of n-hexane, 2,5-hexanedione. The axonal swellings observed in DMHD toxicity are in the proximal axon, as seel Ah iutoxication with ,4l'-iminodipropionitrile, rather tha. ln the distal axon, where neurofilamentous swellings are observed in n-hexane, carbon disulfide, and acrylamide neurotoxicity. In these studies, 14C-labeled DMHD and 2-butanone were synthesized and allowed to react with peripheral nerve. Only 14C-labeled DMHD resulted in stable radiolabeled protein polymers, which were retained by nitrocellulose filters with pore sizes as large as 12 ,um. More specific evidence for covalent crosslinking of neurofilaments was obtained when DMHD was allowed to react with peripheral nerve in which the neurofilaments had been pulse-labeled with L-[35S]methionine.The common solvent, n-hexane, has resulted in sensorimotor neuropathies in industry (1) and after inhalation for its euphoric effects (2). In humans, as well as in experimental animals, the initial alteration is an accumulation of 10-nm neurofilaments in the distal, preterminal axon (3). This is accompanied by huge swellings of the axon, most often proximal to nodes of Ranvier (4). Marked distortions of nodal and paranodal structure are associated with the masses of neurofilaments (5, 6). In large myelinated axons, the neurofilament-filled axonal swellings are followed by Wallerian-like degeneration of the distal axon (4). A similar sequence of events is observed after exposure to carbbn disulfide (7) or acrylamide (8), although with the latter toxicant neurofilament-filled axonal swellings are a less common event. An inherited neuropathy in children, giant axonal neuropathy, is also characterized by neurofilamentous swellings of the distal axon (9). p,B,p-Iminodipropionitrile is a compound that has produced a unique clinical and pathological picture in which the neurofilament-filled axonal swellings occur in the proximal rather than the distal axon (10-12). This proximal axonopathy has been classified separately from the distal axonopathies caused by n-hexane, carbon disulfide, or acrylamide. Similar proximal swellings filled with neurofilaments are seen early in amyotrophic lateral sclerosis (13).The genesis of the neurofilament accumulations in these disorders has been a point of great controversy. Some have postulated that neurofilaments accumulate because of a defect in axonal transport, perhaps secondary to a defect in energy metabolism (14). Cavanagh and Bennetts have suggested that the defect may lie in the catabolism of neurofilaments (15). Studies in this laboratory have led to the proposThe publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertise...
