In vitro evidence that covalent crosslinking of neurofilaments occurs in gamma-diketone neuropathy.

Abstract

It has been 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 .gamma.-diketone, 3,4-dimethyl-2,5-hexanedione (DMHD), is a more potent analog of the toxic metabolite of n-hexane, 2,5-hexanedione. The axonal swellings observed in DMHD toxicity are in the proximal axon, as seen in intoxication with .beta.,.beta.''-iminodipropionitrile, rather than in the distal axon, where neurofilamentous swellings are observed in n-hexane, carbon disulfide and acrylamide neurotoxicity. 14C-labeled DMHD and 2-butanone were synthesized and allowed to react with peripheral nerve [of rat]. Only 14C-labeled DMHD resulted in stable radiolabeled protein polymers, which were retained by nitrocellulose filters with pore sizes as large as 12 .mu.m. 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.