Expression of an endoplasmic reticulum-resident chaperone, glucose-regulated stress protein 78, in the spinal cord of a mouse model of amyotrophic lateral sclerosis.

The immunohistochemical localization of glucose-regulated protein 78/BiP (GRP78), a chaperone protein that primarily resides within the lumen of the endoplasmic reticulum, was investigated in the lumbar spinal cord of mutant copper/zinc superoxide dismutase (SOD1) transgenic mice. Re-staining techniques were used to determine the immunoreactivity with anti-GRP78 antibody of abnormal structures observed by hematoxylin and eosin staining. Besides its physiological localization in the neuronal and glial cytoplasm, GRP78 was expressed in Lewy body-like hyaline inclusions, in irregularly-shaped eosinophilic structures without an apparent halo, and in cord-like swollen neurites. These different sites were invariably also immunopositive for ubiquitin, suggesting them to be pathological structures. The topographic distribution of GRP78 expression closely resembled that of SOD1. Moreover, our chronological quantitative analysis demonstrated that virtually all the Lewy body-like hyaline inclusions were immunolabeled by the anti-GRP78 antibody, irrespective to the age of mice examined, even at the presymptomatic stages. These findings imply that GRP78 may bind to, or at least be closely associated with, SOD1, and may participate in the pathological processes leading to inclusion formation. Thus, the results suggest that dysfunction of GRP78 and subsequent derangement of the system responding to unfolded proteins may be involved in the pathogenesis of familial amyotrophic lateral sclerosis caused by a mutation of the human SOD1 gene.