Neurofilaments Are Nonessential to the Pathogenesis of Toxicant-induced Axonal Degeneration

Overview

Journal J Neurosci

Specialty Neurology

Date 2001 Mar 27

PMID 11264303

Citations 6

Authors

J D Stone

A P Peterson

J Eyer

T G Oblak

D W Sickles

Affiliations

Soon will be listed here.

Abstract

Axonal neurofilament (NF) accumulations occur before development of symptoms and before other pathological changes among idiopathic neurodegenerative diseases and toxic neuropathies, suggesting a cause-effect relationship. The dependence of symptoms and axonal degeneration on neurofilament accumulation has been tested here in a transgenic mouse model (Eyer and Peterson, 1994) lacking axonal NFs and using two prototypic toxicant models. Chronic acrylamide (ACR) or 2,5-hexanedione exposure resulted in progressive and cumulative increases in sensorimotor deficits. Neurobehavioral tests demonstrated similar expression of neurotoxicity in transgenic (T) mice and their nontransgenic (NT) littermates (containing normal numbers of axonal NFs). Axonal lesions were frequently observed after exposure to either toxicant. Quantitation of ACR-induced lesions demonstrated the distal location of pathology and equal susceptibility of T and NT axons. We conclude that axonal NFs have no effect on neurotoxicity and the pattern of pathology in these mammalian toxic neuropathies. These results also suggest that the role of neurofilament accumulation in the pathogenesis of neurodegenerative diseases requires careful evaluation.

Citing Articles

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References

Barnes J . Observations on the effects on rats of compounds related to acrylamide. Br J Ind Med. 1970; 27(2):147-9. PMC: 1009088. DOI: 10.1136/oem.27.2.147. View

DeCaprio A, Olajos E, Weber P . Covalent binding of a neurotoxic n-hexane metabolite: conversion of primary amines to substituted pyrrole adducts by 2,5-hexanedione. Toxicol Appl Pharmacol. 1982; 65(3):440-50. DOI: 10.1016/0041-008x(82)90389-1. View

Hirai T, Mizutani M, Kimura T, Ochiai K, Umemura T, Itakura C . Neurotoxic effects of 2,5-hexanedione on normal and neurofilament-deficient quail. Toxicol Pathol. 1999; 27(3):348-53. DOI: 10.1177/019262339902700311. View

Prineas J . The pathogenesis of dying-back polyneuropathies. II. An ultrastructural study of experimental acrylamide intoxication in the cat. J Neuropathol Exp Neurol. 1969; 28(4):598-621. DOI: 10.1097/00005072-196910000-00004. View

Graham D, St Clair M, Amarnath V, Anthony D . Molecular mechanisms of gamma-diketone neuropathy. Adv Exp Med Biol. 1991; 283:427-31. DOI: 10.1007/978-1-4684-5877-0_58. View

Anthony D, Boekelheide K, Graham D . The effect of 3,4-dimethyl substitution on the neurotoxicity of 2,5-hexanedione. I. Accelerated clinical neuropathy is accompanied by more proximal axonal swellings. Toxicol Appl Pharmacol. 1983; 71(3):362-71. DOI: 10.1016/0041-008x(83)90023-6. View

Sayre L, Gambetti P . Pathogenesis of experimental giant neurofilamentous axonopathies: a unified hypothesis based on chemical modification of neurofilaments. Brain Res. 1985; 357(1):69-83. DOI: 10.1016/0165-0173(85)90008-6. View

Miller R, Lasek R, Katz M . Preferred microtubules for vesicle transport in lobster axons. Science. 1987; 235(4785):220-2. DOI: 10.1126/science.2432661. View

Xu Z, Cork L, Griffin J, Cleveland D . Increased expression of neurofilament subunit NF-L produces morphological alterations that resemble the pathology of human motor neuron disease. Cell. 1993; 73(1):23-33. DOI: 10.1016/0092-8674(93)90157-l. View

10.

Sickles D . Toxic neurofilamentous axonopathies and fast anterograde axonal transport. II. The effects of single doses of neurotoxic and non-neurotoxic diketones and beta, beta'-iminodipropionitrile (IDPN) on the rate and capacity of transport. Neurotoxicology. 1989; 10(1):103-11. View

11.

ODonoghue J, KRASAVAGE W, DiVincenzo G, Katz G . Further studies on ketone neurotoxicity and interactions. Toxicol Appl Pharmacol. 1984; 72(2):201-9. DOI: 10.1016/0041-008x(84)90304-1. View

12.

DeCaprio A, ONeill E . Alterations in rat axonal cytoskeletal proteins induced by in vitro and in vivo 2,5-hexanedione exposure. Toxicol Appl Pharmacol. 1985; 78(2):235-47. DOI: 10.1016/0041-008x(85)90287-x. View

13.

Griffin J, Hoffman P, CLARK A, Carroll P, Price D . Slow axonal transport of neurofilament proteins: impairment of beta,beta'-iminodipropionitrile administration. Science. 1978; 202(4368):633-5. DOI: 10.1126/science.81524. View

14.

Sickles D . Toxic neurofilamentous axonopathies and fast anterograde axonal transport. I. The effects of single doses of acrylamide on the rate and capacity of transport. Neurotoxicology. 1989; 10(1):91-101. View

15.

Sickles D . Toxic neurofilamentous axonopathies and fast anterograde axonal transport. III. Recovery from single injections and multiple dosing effects of acrylamide and 2,5-hexanedione. Toxicol Appl Pharmacol. 1991; 108(3):390-6. DOI: 10.1016/0041-008x(91)90085-s. View

16.

Stone J, Peterson A, Eyer J, Sickles D . Neurofilaments are non-essential elements of toxicant-induced reductions in fast axonal transport: pulse labeling in CNS neurons. Neurotoxicology. 2000; 21(4):447-57. View

17.

FULLERTON P, Barnes J . Peripheral neuropathy in rats produced by acrylamide. Br J Ind Med. 1966; 23(3):210-21. PMC: 1008431. DOI: 10.1136/oem.23.3.210. View

18.

Weaver D, Viancour T . The crayfish neuronal cytoskeleton: an investigation of proteins having neurofilament-like immunoreactivity. Brain Res. 1991; 544(1):49-58. DOI: 10.1016/0006-8993(91)90884-x. View

19.

Sickles D, Goldstein B . Acrylamide alters oxidative enzyme activity in rat motoneurons. Toxicol Lett. 1985; 26(2-3):111-8. DOI: 10.1016/0378-4274(85)90154-7. View

20.

Sickles D, Brady S, Testino A, Friedman M, Wrenn R . Direct effect of the neurotoxicant acrylamide on kinesin-based microtubule motility. J Neurosci Res. 1996; 46(1):7-17. DOI: 10.1002/(SICI)1097-4547(19961001)46:1<7::AID-JNR2>3.0.CO;2-P. View