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

Abstract

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.

New insights into cellular prion protein (PrPc) functions: The “ying and yang” of a relevant protein

“…Prnp knockout mice overexpressing the C-terminal portion of PrP c (lacking OR and CD) of the N-terminal domain (F35 mice) display CGN death, white matter pathology and a progressive and early lethal ataxic phenotype termed Shmerling syndrome (Radovanovic et al, 2005;Shmerling et al, 1998). PCs present no signs of degeneration because of enhancer-mediated splicing that prevents F35 expression in these neurons (Shmerling et al, 1998).…”

“…Similarly to Dpl-mediated degeneration, Shmerling syndrome is rescued by reintroducing the full-length Prnp (Shmerling et al, 1998). However, it has been proposed that myelin pathology induced by N-terminally truncated PrP c acts through independent mechanisms, in contrast to CGN depletion (Radovanovic et al, 2005). Recent studies have shown that overexpression of PrP c devoid of CD or a fragment of CD (residues 105-125) in PrP c knockout mice promotes an exacerbated ataxic syndrome, causing lethality at approximately postnatal day 20 (Baumann et al, 2007;Li et al, 2007b).…”

“…In the brain, maximal Prnp mRNA expression is observed in the adult neocortex and cerebellum. At the cellular level, Prnp is expressed in various neuronal populations of the hippocampus, thalamus and neocortex (Bailly et al, 2004;Harris et al, 1993) and in glial cells (Ford et al, 2002;Laine et al, 2001;Moser et al, 1995;Radovanovic et al, 2005). In neurons, PrP c is predominant in axons and dendrites, excluded from synapse vesicles, and detected in endosomal compartments (Mironov et al, 2003).…”

Prion Neurotoxicity: Insights from Prion Protein Mutants

“…This abnormality, which was also seen Tg(Δ32-134) mice (Radovanovic et al, 2005), may be due either to axonal or myelin damage.…”

Role of prions in neuroprotection and neurodegeneration

“…21,22 Of particular note, these deletion mutants show degeneration of axons and myelin, both in the CNS and in peripheral nerves; indeed some mutants show a predilection for axomyelinic degeneration with little neuronal pathology, 21 suggesting that certain mutated forms of PrP have a direct toxic effect on oligodendrocytes and/or myelin. 23 Moreover, activation of the Dpl1 gene in mice lacking PrP C leads to an ataxic phenotype, that is not observed in the presence of PrP C . 24 Collectively, this indicates that PrP C may act in a protective capacity and in contrast, certain abnormal forms of PrP are "toxic", promoting much more injury to various elements of the CNS and PNS than outright absence of wild-type PrP C .…”