Arsenic inhibits neurofilament transport and induces perikaryal accumulation of phosphorylated neurofilaments: roles of JNK and GSK-3beta.

The environmental neurotoxin arsenic has recently been associated with altered neurofilament (NF) content in sciatic nerve. We examined herein the impact of sodium arsenite (the inorganic form of arsenic) on NF dynamics. Treatment of differentiated NB2/d1 cells and cultured dorsal root ganglion neurons decreased NF transport into axonal neurites and increased perikaryal phospho-NF immunoreactivity. Both of these effects were prevented by a pharmacological inhibitor (SP600125) of c-jun terminal kinase and by expression of a dominant-negative form of this kinase. Arsenic-induced inhibition of NF transport was prevented by treatment with lithium, a selective inhibitor of glycogen synthase kinase-3beta. Pharmacological inhibitors of cyclin-dependent kinase 5 and p38 mitogen-activated protein kinase did not attenuate the effects of arsenic on NF dynamics. These latter findings suggest that this environmental neurotoxin could contribute to peripheral neuropathy by perturbing NF dynamics.