Notch-1 activation and dendritic atrophy in prion disease. Proc Natl Acad Sci U S A

Department of Pathology (Neuropathology), Institute for Neurodegenerative Diseases, University of California, San Francisco, CA 94143, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2005; 102(3):886-91. DOI: 10.1073/pnas.0408612101
Source: PubMed


In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of beta-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established.

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Available from: Erik Samayoa, Jan 28, 2015
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    • "Furthermore, prion infection has been linked to Notch-1 activation in prion-infected cells and brains. Activated Notch-1 inhibits the growth and maturation of axons and dendrites during neuronal development, and can cause their regression after maturation, and it has been associated with dendritic atrophy in prion disease (Ishikura et al., 2005 and references therein). As described above, a number of studies have indicated that synaptic transmission is affected early in prion disease (reviewed in Mallucci, 2009). "
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    ABSTRACT: The cellular prion protein (PrP(C)) is an ubiquitously expressed glycoprotein that is most abundant in the central nervous system. It is thought to play a role in many cellular processes, including neuroprotection, but may also contribute to Alzheimer's disease and some cancers. However, it is best known for its central role in the prion diseases, such as Creutzfeldt-Jakob disease (CJD), bovine spongiform encephalopathy (BSE), and scrapie. These protein misfolding diseases can be sporadic, acquired, or genetic and are caused by refolding of endogenous PrP(C) into a beta sheet-rich, pathogenic form, PrP(Sc). Once prions are present in the central nervous system, they increase and spread during a long incubation period that is followed by a relatively short clinical disease phase, ending in death. PrP molecules can be broadly categorized as either 'good' (cellular) PrP(C) or 'bad' (scrapie prion-type) PrP(Sc), but both populations are heterogeneous and different forms of PrP(C) may influence various cellular activities. Both PrP(C) and PrP(Sc) are localized predominantly at the cell surface, with the C-terminus attached to the plasma membrane via a glycosyl-phosphatidylinositol (GPI) anchor and both can exist in cleaved forms. PrP(C) also has cytosolic and transmembrane forms, and PrP(Sc) is known to exist in a variety of conformations and aggregation states. Here, we discuss the roles of different PrP isoforms in sickness and in health, and show the subcellular distributions of several forms of PrP that are particularly relevant for PrP(C) to PrP(Sc) conversion and prion-induced pathology in the hippocampus. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Feb 2015 · Virus Research
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    • "By the moment, there are two relative studies representing the significant increase in Notch expression activity in sporadic Alzheimer disease (Berezovska et al. 1998; Nagarsheth et al. 2006). Additionally, other neurodegenerative diseases such as Down syndrome (Fischer et al. 2005), Pick's (Nagarsheth et al. 2006) and Prion's disease (Ishikura et al. 2005), are depicted by the increase in Notch expression and amyloid plaques formation. The area that needs to be further investigated concerns the reason that progressive neurodegenerative diseases have different mechanisms in terms of Notch processing and signaling, and whether Notch effectively contributes to their pathobiology. "
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    ABSTRACT: Notch signaling is a master controller of the neural stem cell and neural development maintaining a significant role in the normal brain function. Notch genes are involved in embryogenesis, nervous system, and cardiovascular and endocrine function. On the other side, there are studies representing the involvement of Notch mutations in sporadic Alzheimer disease, other neurodegenerative diseases such as Down syndrome, Pick's and Prion's disease, and CADASIL. This manuscript attempts to present a holistic view of the positive or negative contribution of Notch signaling in the adult brain, and at the same time to present and promote the promising research fields of study.
    Full-text · Article · Jan 2015 · Advances in Experimental Medicine and Biology
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    • "Abnormal conformational changes in the normal cellular prion protein (PrPC) produce the pathogenic forms of prion protein (PrPSc). Accumulation of PrPSc in neuronal membranes, autosomes and lysosomes results in synapse degeneration within a few weeks and nerve cell loss at the later stage of the disease [2]–[4]. "
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    ABSTRACT: Prion disease is caused by a single pathogenic protein (PrPSc), an abnormal conformer of the normal cellular prion protein PrPC. Depletion of PrPC in prion knockout mice makes them resistant to prion disease. Thus, gene silencing of the Prnp gene is a promising effective therapeutic approach. Here, we examined adeno-associated virus vector type 2 encoding a short hairpin RNA targeting Prnp mRNA (AAV2-PrP-shRNA) to suppress PrPC expression both in vitro and in vivo. AAV2-PrP-shRNA treatment suppressed PrP levels and prevented dendritic degeneration in RML-infected brain aggregate cultures. Infusion of AAV2-PrP-shRNA-eGFP into the thalamus of CD-1 mice showed that eGFP was transported to the cerebral cortex via anterograde transport and the overall PrPC levels were reduced by ∼70% within 4 weeks. For therapeutic purposes, we treated RML-infected CD-1 mice with AAV2-PrP-shRNA beginning at 50 days post inoculation. Although AAV2-PrP-shRNA focally suppressed PrPSc formation in the thalamic infusion site by ∼75%, it did not suppress PrPSc formation efficiently in other regions of the brain. Survival of mice was not extended compared to the untreated controls. Global suppression of PrPC in the brain is required for successful therapy of prion diseases.
    Full-text · Article · May 2014 · PLoS ONE
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