Cellular processing of the amyloidogenic cystatin C variant of hereditary cerebral hemorrhage with amyloidosis, Icelandic type

AN important gap in our understanding of the pathogenesis of the amyloidose s is the identification of the cellular events that lead from synthesis of an amyloid precursor protein to its conversion to the amyloid fiber subunit . We address this question by characterizing the effects of an amyloidogeni c mutation on the intracellular processing of its protein product, The prot ein, a mutant of the cysteine protease inhibitor cystatin C, is the amyloid precursor protein in Hereditary Cerebral Hemorrhage with Amyloidosis-Icela ndic type (HCHWA-I). The amyloid fibers are composed of mutant cystatin C ( L68Q) that lades the first 10 amino acids. We have previously shown that pr ocessing of wild-type cystatin C entails formation of a transient intracell ular dimer that dissociates prior to secretion, such that extracellular cys tatin C is monomeric. We report here that the cystatin C mutation engenders several alterations in its intracellular trafficking. It forms a stable in tracellular dime that is partially retained in the endoplasmic reticulum an d degraded. The bulk of mutant cystatin C that is secreted does not dissoci ate and is secreted as an inactive dimer. Thus, formation of the stable mut ant cystatin C dimer is an early event in the pathogenesis of this disease.