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

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.

Scientific Opinion on acrylamide in food

“…The neurotoxic action of AA was suggested to be due to effects on cells of the central and peripheral nervous system including changes in cellular metabolism (Howland et al, 1980;Brimijoin and Hammond,1985;Medrano and LoPachin, 1989;Exon, 2006), changes in gene transcription and protein synthesis (Cavanagh and Nolan, 1982a,b;Cavanagh, 1982;Cavanagh and Gysbers, 1983;Bisby and Redshaw, 1987;Lin et al, 2000;El-Alfy et al, 2011;Seale et al, 2012), effects on neurotransmitter levels and turn-over (Dixit et al, 1981;Uphouse and Russell, 1981;Aldous et al, 1983;Shi et al, 2012), binding to cellular proteins including damage to microtubular and neurofilamental proteins (Hashimoto and Aldridge, 1970;Tanii and Hashimoto, 1983;Carrington et al, 1991;Reagan et al, 1994;Abou-Donia, 1996, 1997;Lapadula et al, 1989;Xiwen et al, 1992), changes in ion distribution (Lehning et al, 1998;LoPachin and Lehning, 1994), and axonal transport (Chretien et al, 1981;Miller and Spencer, 1984;Gold et al, 1985;Moretto and Sabri, 1988;Logan and McLean, 1988;Harry et al, 1989;Sabri and Spencer, 1990;Martenson et al, 1995;Sickles et al, 1995Sickles et al, ,1996Stone et al, 2001). However, the minimal effects of AA-treatment, by up to a maximally tolerated dose, on: (i) gene expression related to cholinergic, noradrenergic, dopaminergic, GABAergic, or glutamatergic neurotransmitter systems; (ii) neurotransmitter levels related ...…”

Review of the Multiple Aspects of Neurofilament Functions, and their Possible Contribution to Neurodegeneration

“…The administration of acrylamide also increases the expression of mRNA for NF proteins and the phosphorylation of NF in rats [444][445][446] but decreases their degradation [447]. However, acrylamide-induced neurotoxicity is not initiated exclusively through its action on axonal NF because NF-deficient mutant quiver quails, crayfish (a species lacking NF) and NFH-LacZ mice are sensitive to neurotoxic effects of acrylamide [448][449][450].…”

Synaptic dysfunction in disease and following injury in the developing and adult nervous system: Caveats in the choice of therapeutic intervention☆

“…ACR toxicity results in the accumulation of NFs, swelling of distal axons, increase in tubulovesicular bodies and progressive senorimotor impairment (Prineas, 1969;Spencer and Schaumburg, 1974). However, ACR causes similar behavioral impairment, axonal pathology and transport defects in mice genetically lacking NFs, suggesting that disruption of NFs is not required for ACR-mediated toxicity (Stone et al, 2001). Evidence suggesting that ACR-mediated toxicity acts specifically at the synapse comes from a study which observed terminal degeneration and behavioral deficits in the absence of any degenerative changes in the axon (Lehning et al, 2003).…”