Dimethylhexanedione impairs the movement of neurofilament protein subunits, NFM and NFL, in the optic system
Pyle, S.J.; Graham, D.G.; Anthony, D.C.
Neurotoxicology 15(2): 279-286
1994
ISSN/ISBN: 0161-813X PMID: 7991216 Document Number: 432021
Exposure to the neurotoxic gamma-diketone 3,4-dimethyl-2,5-hexanedione (DMHD) leads to the accumulation of neurofilaments within the proximal axon and to an inhibition in the rate of anterograde transport of recently synthesized neurofilaments. These effects of DMHD are similar to those of the neurotoxic nitrile 3,3'-iminodipropionitrile (IDPN), which is also characterized by formation of neurofilamentous swellings within the proximal axon and an inhibition of transport, both of newly synthesized neurofilaments and those already in transit in more distal regions of the axon. Due to the similarities between these compounds, DMHD also might be expected to inhibit neurofilament transport in the distal axon. The objective of this study was to examine the effects of DMHD on the movement of labeled neurofilament proteins which were in transit at the time of intoxication. Proteins in the optic system, pulse labeled with 35S-methionine, underwent transport for two weeks prior to the start of intoxication. Neurofilament transport was assessed by SDS-PAGE fluorography and computerized densitometry. At two and five weeks in control animals the peaks of NFL and NFM neurofilament subunits had broadened and flattened from their original proximal location and assumed a more uniform, proximodistal distribution (peak dispersion). In contrast, in DMHD-treated animals, the radiolabeled NFL and NFM remained near their position at the start of intoxication, retaining a peak of radiolabeled protein. A proportion of each of the subunits, however, had entered the distal axon during intoxication suggesting that a population of filaments may remain transport competent. These findings indicate that DMHD, in a pattern completely analogous to IDPN, impairs the anterograde transport of neurofilament proteins, both those recently synthesized which accumulate within the proximal axon and those that are already in transit at the time of intoxication.