The prion protein is neuroprotective against retinal degeneration in vivo

Frigg, Rico; Wenzel, Andreas; Samardzija, Marijana; Oesch, Bruno; Wariwoda, Hedwig; Navarini, Alexander A.; Seeliger, Mathias W.; Tanimoto, Naoyuki; Remé, Charlotte E.; Grimm, Christian

doi:10.1016/j.exer.2006.07.010

Cited by 15 publications

(11 citation statements)

References 49 publications

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“…It has been shown that lectin binding and normal prion (PrP C ) glycosylation are altered during aging [33]. STAT1 transcription factor signaling is increased in mouse models lacking PrP C , indicating a neuroprotective role of PrP C [34,35]. The STAT3 transcription factor is important for the anti-apoptotic activity of humanin and therefore for humanin-mediated neuroprotection after Alzheimer disease-related insult [36].…”

Section: Discussionmentioning

confidence: 99%

Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease

et al. 2012

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BackgroundThe activation of immune cells in the brain is believed to be one of the earliest events in prion disease development, where misfolded PrionSc protein deposits are thought to act as irritants leading to a series of events that culminate in neuronal cell dysfunction and death. The role of these events in prion disease though is still a matter of debate. To elucidate the mechanisms leading from abnormal protein deposition to neuronal injury, we have performed a detailed network analysis of genes differentially expressed in several mouse prion models.ResultsWe found a master regulatory core of genes related to immune response controlling other genes involved in prion protein replication and accumulation, and neuronal cell death. This regulatory core determines the existence of two stable states that are consistent with the transcriptome analysis comparing prion infected versus uninfected mouse brain. An in silico perturbation analysis demonstrates that core genes are individually capable of triggering the transition and that the network remains locked once the diseased state is reached.ConclusionsWe hypothesize that this locking may be the cause of the sustained immune response observed in prion disease. Our analysis supports the hypothesis that sustained brain inflammation is the main pathogenic process leading to neuronal dysfunction and loss, which, in turn, leads to clinical symptoms in prion disease.

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Section: Discussionmentioning

confidence: 99%

Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease

et al. 2012

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“…Intriguingly, PrP C has been reported to inhibit activity of NMDARs containing the GluN2D subunit, which suggests that PrP C may protect neurons from excitotoxic death (Khosravani et al, 2008). There is evidence for this in vivo , for example, Zurich I PrP C -knockout mice displayed increased excitotoxicity in the retina in response to damaging light intensities (Frigg et al, 2006) and in the hippocampus following injection with N-methyl-D-aspartate (Khosravani et al, 2008), which selectively activates NMDARs. Given that excitotoxicity is the major cause of neuronal death following ischaemic stroke (Lai et al, 2014), it is also interesting to note that experimental stroke has been shown to induce PrP C expression in the affected brain region in both rats and mice (Weise et al, 2004; Shyu et al, 2005).…”

Section: Prpc Functionmentioning

confidence: 99%

Physiological Functions of the Cellular Prion Protein

Castle

Gill

2017

Front. Mol. Biosci.

163

157

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The prion protein, PrPC, is a small, cell-surface glycoprotein notable primarily for its critical role in pathogenesis of the neurodegenerative disorders known as prion diseases. A hallmark of prion diseases is the conversion of PrPC into an abnormally folded isoform, which provides a template for further pathogenic conversion of PrPC, allowing disease to spread from cell to cell and, in some circumstances, to transfer to a new host. In addition to the putative neurotoxicity caused by the misfolded form(s), loss of normal PrPC function could be an integral part of the neurodegenerative processes and, consequently, significant research efforts have been directed toward determining the physiological functions of PrPC. In this review, we first summarise important aspects of the biochemistry of PrPC before moving on to address the current understanding of the various proposed functions of the protein, including details of the underlying molecular mechanisms potentially involved in these functions. Over years of study, PrPC has been associated with a wide array of different cellular processes and many interacting partners have been suggested. However, recent studies have cast doubt on the previously well-established links between PrPC and processes such as stress-protection, copper homeostasis and neuronal excitability. Instead, the functions best-supported by the current literature include regulation of myelin maintenance and of processes linked to cellular differentiation, including proliferation, adhesion, and control of cell morphology. Intriguing connections have also been made between PrPC and the modulation of circadian rhythm, glucose homeostasis, immune function and cellular iron uptake, all of which warrant further investigation.

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“…PrP C expression levels increase after these kinds of injury and lesion size is larger in Prn-p 0/0 compared to wild-type mice [ 20 , 21 ]. Retinal photoreceptors from Prn-p 0/0 mice have also been reported to be more susceptible to light-induced apoptosis [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

Prion protein lacks robust cytoprotective activity in cultured cells

Christensen

2008

Molecular Neurodegeneration

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Background: The physiological function of the cellular prion protein (PrP C ) remains unknown. However, PrP C has been reported to possess a cytoprotective activity that prevents death of neurons and other cells after a toxic stimulus. To explore this effect further, we attempted to reproduce several of the assays in which a protective activity of PrP had been previously demonstrated in mammalian cells.

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The prion protein is neuroprotective against retinal degeneration in vivo

Cited by 15 publications

References 49 publications

Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease

Gene regulatory network analysis supports inflammation as a key neurodegeneration process in prion disease

Physiological Functions of the Cellular Prion Protein

Prion protein lacks robust cytoprotective activity in cultured cells

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