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.

Prion and doppel proteins bind to granule cells of the cerebellum / Legname, G.; Nelken, P.; Guan, Z.; Kanyo, Z. F.; Dearmond, S. J.; Prusiner, S. B.. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - 99:25(2002), pp. 16285-16290. [10.1073/pnas.242611999]

Prion and doppel proteins bind to granule cells of the cerebellum

Legname, G.;
2002-01-01

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.
2002
99
25
16285
16290
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC138603/
Legname, G.; Nelken, P.; Guan, Z.; Kanyo, Z. F.; Dearmond, S. J.; Prusiner, S. B.
File in questo prodotto:
File Dimensione Formato  
Legname_PNAS_2002.pdf

non disponibili

Tipologia: Versione Editoriale (PDF)
Licenza: Non specificato
Dimensione 298.24 kB
Formato Adobe PDF
298.24 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11767/16953
Citazioni
  • ???jsp.display-item.citation.pmc??? 6
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 20
social impact