title: Prion and doppel proteins bind to granule cells of the cerebellum.
abstract: We reported that expression of the cellular prion protein (PrPC) rescues doppel (Dpl)-induced cerebellar degeneration in mice. To search for protein(s) that mediate this process, we fused the C-termini of mouse (Mo) PrP and Dpl to the Fc portion of an IgG. Although both MoPrP-Fc and MoDpl-Fc bound to many regions of the brain, we observed restricted binding to granule cells in the cerebellum, suggesting a scenario in which granule cells express a protein that mediates Dpl-induced neurodegeneration. Because granule cells do not express PrPC, it seems unlikely that MoPrP-Fc binding reflects a ligand that is involved in the conversion of PrPC into PrPSc, the disease-causing isoform. In contrast, the dominant-negative MoPrP(Q218K)-Fc not only binds to granule cells but also binds to neurons of the molecular layer where PrPC is expressed. These findings raise the possibility that the cells of the molecular layer express an auxiliary protein, provisionally designated protein X, which is involved in prion formation and is likely to be distinct from the protein that mediates Dpl-induced degeneration. Although the binding of the dominant-negative MoPrP(Q218K)-Fc to cells in the molecular layer expressing PrPC is consistent with a scenario for the binding of MoPrP(Q218K)-Fc to protein X, the absence of PrPSc deposition in the molecular layer requires that PrP(Sc), once formed there, be readily transported to the cerebellar white matter where PrPSc is found. Identifying the ligands to which PrP-Fc, Dpl-Fc, and dominant-negative PrP bind may provide new insights into the functions of PrPC and Dpl as well as the mechanism of PrPSc formation.
authors.affiliation: Institute for Neurodegenerative Diseases and Departments of Neurology, University of California, San Francisco, CA 94143, USA.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Legname
authors.forename: Peter
authors.initials: P
authors.lastname: Nelken
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Guan
authors.forename: Zoltan F
authors.initials: ZF
authors.lastname: Kanyo
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: DeArmond
authors.forename: Stanley B
authors.initials: SB
authors.lastname: Prusiner
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D002531:Cerebellum / Q000166:cytology*; D058851:GPI-Linked Proteins; D018390:Gene Targeting; D005799:Genes, Dominant; D006031:Glycosylation; D006801:Humans; D007141:Immunoglobulin Fc Fragments / Q000235:genetics; D051379:Mice; D009410:Nerve Degeneration; D009474:Neurons / Q000378:metabolism*; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D018621:PrPC Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D018620:PrPSc Proteins / Q000096:biosynthesis; D011328:Prions / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D001685:Biological Factors; D058851:GPI-Linked Proteins; D007141:Immunoglobulin Fc Fragments; C501125:PRND protein, human; D010446:Peptide Fragments; D018621:PrPC Proteins; D018620:PrPSc Proteins; D011328:Prions; C122036:Prnd protein, mouse; D011993:Recombinant Fusion Proteins