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The Journal of Neuroscience, April 1, 2001, 21(7):2278-2287

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

J. Derek Stone¹, Alan P. Peterson², Joel Eyer³, T. Gregory Oblak¹, and Dale W. Sickles¹

¹ Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, Georgia 30912, ² Department of Neurology and Neurosurgery and Molecular Oncology Group, McGill University, Montreal H3A 1A1, Canada, and ³ Institut National de la Santé et de la Recherche Médicale, Centre Hospitalier Universitaire, 49033 Angers, France

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.

Key words: neurofilaments; acrylamide; 2,5-hexanedione; -diketones; neuropathies; transgenic mice

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2172278-10$05.00/0

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