DECREASED INSULIN-LIKE GROWTH-FACTOR I-MEDIATED PROTEIN-TYROSINE PHOSPHORYLATION IN HUMAN OLIVOPONTOCEREBELLAR ATROPHY AND LURCHER MUTANT MOUSE

We examined insulin-like growth factor I (IGF-I)-dependent phosphoryla tion and protein tyrosine kinase (PTK) activity in cerebellar cortex o f normal humans, patients: with olivopontocerebellar atrophy (OPCA) (' 'C'' kindred) and in lurcher mutant mouse, a suggested animal model fo r OPCA. PTK activity and IGF-I-dependent protein tyrosine phosphorylat ion was significantly reduced in cerebellar cortex of human OPCA patie nts as compared to the normal controls. Immunoblot analysis also demon strated a decrease in cerebellar 80 kDa phosphotyrosine protein in the se patients. By autoradiography, IGF-I receptors were localized in the molecular layer of 30-day-old control and lurcher mutant mice cerebel la. However, the lurcher mutant mice showed a decrease in [I-125]-IGF- I binding in the molecular layer as compared to the littermate control s. The IGF-I receptor autophosphorylation was also markedly reduced in 15-day- and 22-day-old lurcher cerebella. These results suggest that the process of cerebellar degeneration in human OPCA and lurcher mutan t mouse may be associated with altered IGF-I receptor binding and prot ein tyrosine phosphorylation.