Purkinje-cell degeneration in prion protein-deficient mice is associated with a cerebellum-specific Doppel protein species signature

PrPc (cellular prion protein) and Doppel are antagonizing proteins, respectively neuroprotective and neurotoxic. Evidence for Doppel neurotoxicity came from PrPc-deficient (Prnp0/0) mouse lines developing late onset Purkinje-cell degeneration caused by Doppel overexpression in brain. To address the molecular underpinnings of this cell-type specificity, we generated Doppel N-terminal-specific antibodies and started to examine the spatio-temporal expression of Doppel protein species in Ngsk Prnp0/0 brain. Although Doppel overexpression is ubiquitous, Western analyses of normal and deglycosylated protein extracts revealed cerebellar patterns distinct from the rest of the brain, supporting the idea that neurotoxicity might be linked to a particular Doppel species pattern. Furthermore, our newly raised antibodies allowed the first Doppel immunohistochemical analyses in brain, showing a distribution in Prnp0/0 cerebellum similar to PrPc in wild type.