L-homocysteic acid as an alternative cytotoxin for studying glutamate-induced cellular degeneration of Huntington's disease and normal skin fibroblasts

Abstract

Huntington's Disease (HD) and normal skin fibroblasts in culture were exposed to several acidic amino acids structurally related to L-glutamate which have excitotoxic properties in the nervous system. L-Homocysteic acid, a sulfonic acid analogue of glutamate, was the only other acidic amino acid causing fibroblast degeneration similar to that induced by glutamate. None of the other compounds tested, including the D isomer of homocysteic acid, were as toxic as 30 mM glutamate. As previously noted with glutamate treatment, HD fibroblasts demostrated an increased sensitivity to L-homocysteic acid compared to controls. In contrast to glutamate, no cellular metabolism of L-homocysteic acid could be detected; a property which may account for the increased cytotoxicity of L-homocysteic acid compared to glutamate. The identification of L-homocysteic acid, a glutamate analogue which undergoes limited metabolism, should enable the elucidation of the toxic mechanism of glutamate and facilitate the determination of the site conferring increased sensitivity of cultured HD fibroblasts to glutamate.