Targeting Cellular Prion Protein Reverses Early Cognitive Deficits and Neurophysiological Dysfunction in Prion-Infected Mice

University of Birmingham, Birmingham, England, United Kingdom
Neuron (Impact Factor: 15.05). 03/2007; 53(3):325-35. DOI: 10.1016/j.neuron.2007.01.005
Source: PubMed


Currently, no treatment can prevent the cognitive and motor decline associated with widespread neurodegeneration in prion disease. However, we previously showed that targeting endogenous neuronal prion protein (PrP(C)) (the precursor of its disease-associated isoform, PrP(Sc)) in mice with early prion infection reversed spongiform change and prevented clinical symptoms and neuronal loss. We now show that cognitive and behavioral deficits and impaired neurophysiological function accompany early hippocampal spongiform pathology. Remarkably, these behavioral and synaptic impairments recover when neuronal PrP(C) is depleted, in parallel with reversal of spongiosis. Thus, early functional impairments precede neuronal loss in prion disease and can be rescued. Further, they occur before extensive PrP(Sc) deposits accumulate and recover rapidly after PrP(C) depletion, supporting the concept that they are caused by a transient neurotoxic species, distinct from aggregated PrP(Sc). These data suggest that early intervention in human prion disease may lead to recovery of cognitive and behavioral symptoms.

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Available from: Melanie White, Oct 03, 2015
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    • "Synaptic dysfunction is found in the early phase of AD, and loss of synapses appears in the later phase. As a result, the excitatory transmission in hippocampus and cerebral cortex is inhibited, which contributes to memory loss [27] [28]. Although Aí µí»½ deposition may cause neuron loss, the main way of neuron-synapse loss is apoptosis. "
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    BioMed Research International 11/2014; 2014:350516. DOI:10.1155/2014/350516 · 3.17 Impact Factor
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    • "The link between the proteasome and PrP appears to be physiologically significant since PrPSc impairs proteasomal activities, which are essential to cell growth and survival [11], [13], [17]. Importantly, it was shown that tuning down PrP expression can reverse the progression of disease even after its onset [25], [26]. Our data not only provide new insights regarding the mechanism governing PrP regulation, but also lay the foundation for unraveling the specific roles of Ub-mediated proteolysis in prion biogenesis and pathogenesis. "
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    ABSTRACT: Prion protein PrP is a central player in several devastating neurodegenerative disorders, including mad cow disease and Creutzfeltd-Jacob disease. Conformational alteration of PrP into an aggregation-prone infectious form PrPSc can trigger pathogenic events. How levels of PrP are regulated is poorly understood. Human PrP is known to be degraded by the proteasome, but the specific proteolytic pathway responsible for PrP destruction remains elusive. Here, we demonstrate that the ubiquitin ligase gp78, known for its role in protein quality control, is critical for unglycosylated PrP ubiquitylation and degradation. Furthermore, C-terminal sequences of PrP protein are crucial for its ubiquitylation and degradation. Our study reveals the first ubiquitin ligase specifically involved in prion protein PrP degradation and PrP sequences crucial for its turnover. Our data may lead to a new avenue to control PrP level and pathogenesis.
    PLoS ONE 04/2014; 9(4):e92290. DOI:10.1371/journal.pone.0092290 · 3.23 Impact Factor
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    • "NeuN immunhistochemical analysis showed a better neuronal survival in mice treated with the PrP-siRNA compared to both control without reaching the statistical significance between PrP-siRNA and scrambled-siRNA groups. This result is consistent with those observed by Mallucci et al. [10], [11] showing down regulation of PrPC expression using lentiviral expression vectors carrying PrP-shRNA. In this study, the lentivector carrying PrPshRNA was able to reduce PrP expression in mouse brains in the vicinity of the injection site, to rescue neuronal damages mainly in the area treated and to reverse the pathological phenotype in prion infected mice. "
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