Mechanisms of neurotoxicity related to selective disruption of microtubules and intermediate filaments

The neuronal response to several neurotoxic chemicals includes disruption of the cytoskeleton such as interactions with microtubules and altered distribution of neurofilaments. Methylmercury (microtubule disrupting) and acrylamide and 2,5-hexanedione (neurofilament disrupting) have been used in a cell culture (PtK2) system to distinguish the cytoskeletal targets of these compounds. Methylmercury caused disassembly of microtubules with secondary collapse of vimentin filaments (epithelial cell equivalent of neurofilaments) at higher concentrations; actin filaments were unaltered. This confirms that disruption of actin does not contribute to methylmercury-induced interference with mitosis. In contrast, both acrylamide and 2,5-hexanedione caused a perinuclear redistribution of vimentin filaments with sparing of microtubules. Biochemical studies revealed that 2,5-hexanedione treatment resulted in high molecular weight vimentin-immunoreactive species, presumably by cross-linking of proteins. Selective action of both acrylamide and 2,5-hexanedione on vimentin filaments and the similarity of effects suggest that a common mechanism of damage may occur whereby these compounds act directly on both vimentin and neurofilaments.