Inhibition of Brain Protein Synthesis

Abstract

An understanding of the molecular basis of normal and altered neurological function represents one of the significant challenges of modern neurology. In many neurologic disorders we can specify the enzymatic defect and the resultant alterations in precursors and products. But even in conditions so defined it remains unclear what altered brain functions produce the devastating neurologic disorder. The amino acidurias serve as an excellent example of disorders whose enzymatic and neuropathologie defects are reasonably well delineated, but whose brain dysfunction cannot be defined biochemically.(1) Alterations in neurohormones and in mitochondrial function have been implicated, but not proven.(2–6) For our present purposes the most intriguing hypotheses relate to alterations in protein synthesis which may occur as the result of amino acid imbalances.(7,8) In this report we review some of our experimental data which confirm reported alterations in amino acid transport produced by amino acid imbalances,(9–12) and suggest that both by inhibition of transport and by interference with amino acid activation, a significant inhibition of protein synthesis may occur in vitro Assuming that protein synthesis is a rate-limiting reaction in brain function, studies of amino acid inhibition in vitro may represent a meaningful approach to the understanding of neurologic dysfunction at a molecular level.