Disruption of Doppel prevents neurodegeneration in mice with extensive
            <i>Prnp</i>
            deletions

Genoud, Nicolas; Behrens, Axel; Miele, Gino; Robay, Dimitri; Heppner, Frank L.; Freigang, Stefan; Aguzzi, Adriano

doi:10.1073/pnas.0400131101

Cited by 41 publications

(36 citation statements)

References 42 publications

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“…The hematocrits, hemoglobin levels, and total red and white blood cell levels in peripheral blood were similar in the PrP-null and control mice ( Table 2, which is published as supporting information on the PNAS web site). Furthermore, BM cells were reacted with various lineage-specific antibodies, and the cells were analyzed by flow cytometry; we found no differences in staining profiles between the two types of animals (data not shown), consistent with prior observations (19). We assayed PrP-null and WT BM cells for colony-forming units (CFUs) to look for defects in progenitor numbers or activities.…”

Section: Prp Is a Marker For Long-term (Lt) Hscssupporting

confidence: 56%

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Zhang

Steele

Lindquist

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

210

196

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Section: Prp Is a Marker For Long-term (Lt) Hscssupporting

confidence: 56%

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Zhang

Steele

Lindquist

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

210

196

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“…The overlapping patterns of (1) Dpl-and ⌬PrP-induced leukoencephalopathy, (2) their modulation by coexpression of fulllength PrP C (Moore et al, 1999;Li et al, 2000;Rossi et al, 2001), (3) the structural homology between Dpl and ⌬PrP (Luhrs et al, 2003), and (4) the abrogation of neurodegeneration by removal of Dpl from Prnp ZHII/ZHII mice (Genoud et al, 2004) all suggest that ⌬PrP and Dpl trigger similar pathogenetic mechanisms. What might be the common structural basis of such pathologies?…”

Section: Discussionmentioning

confidence: 99%

“…In homozygous Prnp ZHII/ZHII and in compound heterozygous Prnp ZHII/o mice, loxP-mediated deletion of the entire third Prnp exon induces atypical intergenic splicing patterns that place Dpl under transcriptional control of the Prnp promoter, thereby leading to Dpl overexpression in brain (Weissmann and Aguzzi, 1999;Rossi et al, 2001). Overexpression of Prnd leads to cerebellar degeneration, possibly by similar mechanisms as ⌬PrP (Moore et al, 1999;Genoud et al, 2004). We therefore analyzed the white matter of 18-month-old Prnp ZHII/o mice with advanced clinical disease.…”

Section: White-matter Pathology In Prnpmentioning

confidence: 99%

Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrP^C

et al. 2005

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The cellular prion protein PrP C confers susceptibility to transmissible spongiform encephalopathies, yet its normal function is unknown. Although PrP C -deficient mice develop and live normally, expression of amino proximally truncated PrP C (⌬PrP) or of its structural homolog Doppel (Dpl) causes cerebellar degeneration that is prevented by coexpression of full-length PrP C . We now report that mice expressing ⌬PrP or Dpl suffer from widespread leukoencephalopathy. Oligodendrocyte-specific expression of full-length PrP C under control of the myelin basic protein (MBP) promoter repressed leukoencephalopathy and vastly extended survival but did not prevent cerebellar granule cell (CGC) degeneration. Conversely, neuron-specific PrP C expression under control of the neuron-specific enolase (NSE) promoter antagonized CGC degeneration but not leukoencephalopathy. PrP C was found in purified myelin and in cultured oligodendrocytes of both wild-type and MBP-PrP transgenic mice but not in NSE-PrP mice. These results identify white-matter damage as an extraneuronal PrP-associated pathology and suggest a previously unrecognized role of PrP C in myelin maintenance.

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“…ϩ expansions after lymphocytic choriomeningitis virus (LCMV) infection and specific antibody production after infection with LCMV or vesicular stomatitis virus (22). However, the range of infectious and immunological challenges to which PrP knockouts have been exposed is limited.…”

Section: Mice Lacking Both Prp and Its Downstream Partial Homolog Dopmentioning

confidence: 99%

A role of cellular prion protein in programming T‐cell cytokine responses in disease

et al. 2009

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The cellular prion protein (PrPC) is widely expressed in neural and non‐neural tissues, but its function is unknown. Elucidation of the part played by PrPC in adaptive immunity has been a particular conundrum: increased expression of cell surface PrPChas been documented during T‐cell activation, yet the functional significance of this activation remains unclear, with conflicting data on the effects of Prnp gene knockout on various parameters of T‐cell immunity. We show here that Prnp mRNA is highly inducible within 8‐24 h of T‐cell activation, with surface protein levels rising from 24 h. When measured in parallel with CD69 and CD25, PrPC is a late activation antigen. Consistent with its up‐regulation being a late activation event, PrP deletion did not alter T‐cell‐antigen presenting cell conjugate formation. Most important, activated PrP0/0T cells demonstrated much reduced induction of several T helper (Th) 1, Th2, and Th17 cytokines, whereas others, such as TNF‐α and IL‐9, were unaffected. These changes were investigated in the context of an autoimmune model and a bacterial challenge model. In experimental autoimmune encephalomyelitis, PrP‐knockout mice showed enhanced disease in the face of reduced IL‐17 responses. In a streptococcal sepsis model, this constrained cytokine program was associated with poorer local control of infection, although with reduced bacteremia. The findings indicate that PrPC is a potentially important molecule influencing T‐cell activation and effector function.—Ingram, R.J., Isaacs, J.D., Kaur, G., Lowther, D.E., Reynolds, C.J., Boyton,R. J., Collinge, J., Jackson, G.S., Altmann, D.M. A role of cellular prion protein in programming T‐cell cytokine responses in disease. FASEB J. 23, 1672–1684 (2009)

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Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions

Cited by 41 publications

References 42 publications

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrP^C

A role of cellular prion protein in programming T‐cell cytokine responses in disease

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Disruption of Doppel prevents neurodegeneration in mice with extensive Prnp deletions

Cited by 41 publications

References 42 publications

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Prion protein is expressed on long-term repopulating hematopoietic stem cells and is important for their self-renewal

Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrPC

A role of cellular prion protein in programming T‐cell cytokine responses in disease

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Product

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Truncated Prion Protein and Doppel Are Myelinotoxic in the Absence of Oligodendrocytic PrP^C