Copper chaperone for superoxide dismutase co-aggregates with superoxide dismutase 1 (SOD1) in neuronal Lewy body-like hyaline inclusions: an immunohistochemical study on familial amyotrophic lateral sclerosis with SOD1 gene mutation

The copper chaperone for superoxide dismutase (CCS) interacts with Cu/Zn-bi nding superoxide dismutase 1 (SOD1) specifically and delivers copper to SOD 1. To determine the role of the CCS-SOD1 interaction in the pathogenesis of SOD1-mutated familial amyotrophic lateral sclerosis (FALS) patients, we pr oduced an affinity-purified rabbit antibody against CCS and investigated th e immunohistochemical localization of both CCS and SOD 1 in neuronal Lewy b ody-like hyaline inclusions (LBHIs) in the spinal cords of two FALS patient s with a two-base pair deletion at codon 126 in the SOD1 gene and three FAL S patients with an Ala to Val substitution at codon 4. The LBHIs in anterio r horn cells from the five FALS patients showed identical immunoreactivitie s for CCS: the reaction product deposits with the antibody against CCS were generally restricted to the periphery of the core and halo-type LBHIs. The localizations of the immunoreactivities for CCS and SOD1 were similar in t he inclusions: both CCS and SOD1 colocalized in neuronal LBHIs in the five mutant SOD1-linked FALS patients. Our results suggest that the specific int eraction and aggregation of CCS-SOD1 (probably CCS-mutant SOD1) in SOD1-mut ated FALS patients may amplify the formation of inclusions and emphasize a more marked mutant SOD l-mediated toxicity.