Up-regulation of functionally impaired insulin-like growth factor-1 receptor in scrapie-infected neuroblastoma cells

A growing body of evidence suggests that an altered level or function of th e neurotrophic insulin-like growth factor-1 receptor (IGF-1R), which suppor ts neuronal survival, may underlie neurodegeneration. This study has focuse d on the expression and function of the IGF-1R in scrapie-infected neurobla stoma cell lines. Our results show that scrapie infection induces a 4-fold increase in the level of IGF-1R in two independently scrapie-infected neuro blastomas, ScN2a and ScN1E-115 cells, and that the increased IGF-1R level w as accompanied by increased IGF-1R mRNA levels. In contrast to the elevated IGF-IR expression in ScN2a, receptor binding studies revealed an 80% decre ase in specific I-125-IGF-1-binding sites compared with N2a cells. This dec rease in IGF-1R-binding sites was shown to be caused by a 7-fold decrease i n IGF-1R affinity. Furthermore, ScN2a showed no significant difference in I GF-1 induced proliferative response, despite the noticeable elevated IGF-1R expression, putatively explained by the reduced IGF-1R binding affinity. A dditionally, IGF-1 stimulated IGF-1R beta tyrosine phosphorylation showed n o major change in the dose-response between the cell types, possibly due to altered tyrosine kinase signaling in scrapie-infected neuroblastoma cells. Altogether these data indicate that scrapie infection affects the expressi on, binding affinity, and signal transduction mediated by the IGF-1R in neu roblastoma cells. Altered IGF-1R expression and function may weaken the tro phic support in scrapie-infected neurons and thereby contribute to neurodeg eneration in prion diseases.