EXPRESSION OF AMINO-TERMINALLY TRUNCATED PRP IN THE MOUSE LEADING TO ATAXIA AND SPECIFIC CEREBELLAR LESIONS

The physiological role of prion protein (PrP) remains unknown. Mice de void of PrP develop normally but are resistant to scrapie; introductio n of a PrP transgene restores susceptibility to the disease. To identi fy the regions of PrP necessary for this activity, we prepared PrP kno ckout mice expressing PrPs with amino-proximal deletions. Surprisingly , PrP lacking residues 32-121 or 32-134, but not with shorter deletion s, caused severe ataxia and neuronal death limited to the granular lay er of the cerebellum as early as 1-3 months after birth. The defect wa s completely abolished by introducing one copy of a wild-type PrP gene . We speculate that these truncated PrPs may be nonfunctional and comp ete with some other molecule with a PrP-like function for a common lig and.