Loss of Prion Protein Leads to Age-Dependent Behavioral Abnormalities and Changes in Cytoskeletal Protein Expression

Schmitz, Matthias; Greis, Catharina Marlies; Ottis, Philipp; Silva, Christopher J.; Schulz‐Schaeffer, Walter; Wrede, Arne; Koppe, Katharina; Onisko, Bruce; Requena, Jesús R.; Govindarajan, Nambirajan; Korth, Carsten; Fischer, André; Zerr, Inga

doi:10.1007/s12035-014-8655-3

Cited by 35 publications

(64 citation statements)

References 53 publications

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“…In vivo, the changes observed in embryos lacking PrP C may altogether favor a precocious differentiation of neural stem/progenitor cells (see above). The subtle and transient defects occurring in the developing CNS of Prnp 2/2 mice could actually account for the behavioral and cognitive deficits recorded in mice lacking PrP C [52], in line with the proposed neurodevelopmental origin of psychiatric disorders [53]. Another hypothesis that would be worth considering is that the absence of PrP C disturbs the homeostasis of adult neural stem cells, since Notch signaling controls neural stem cell maintenance in the adult brain as well [54].…”

Section: Discussionmentioning

confidence: 66%

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

et al. 2016

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The prion protein is infamous for its involvement in a group of neurodegenerative diseases known as Transmissible Spongiform Encephalopathies. In the longstanding quest to decipher the physiological function of its cellular isoform, PrP , the discovery of its participation to the self-renewal of hematopoietic and neural stem cells has cast a new spotlight on its potential role in stem cell biology. However, still little is known on the cellular and molecular mechanisms at play. Here, by combining in vitro and in vivo murine models of PrP depletion, we establish that PrP deficiency severely affects the Notch pathway, which plays a major role in neural stem cell maintenance. We document that the absence of PrP in a neuroepithelial cell line or in primary neurospheres is associated with drastically reduced expression of Notch ligands and receptors, resulting in decreased levels of Notch target genes. Similar alterations of the Notch pathway are recovered in the neuroepithelium of Prnp embryos during a developmental window encompassing neural tube closure. In addition, in line with Notch defects, our data show that the absence of PrP results in altered expression of Nestin and Olig2 as well as N-cadherin distribution. We further provide evidence that PrP controls the expression of the epidermal growth factor receptor (EGFR) downstream from Notch. Finally, we unveil a negative feedback action of EGFR on both Notch and PrP . As a whole, our study delineates a molecular scenario through which PrP takes part to the self-renewal of neural stem and progenitor cells. Stem Cells 2017;35:754-765.

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Section: Discussionmentioning

confidence: 66%

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

et al. 2016

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“…13 Furthermore, their nest building abilities were significantly poorer than WT controls. 12 These findings were initially observed in a Prnp0/0 mouse line with a mixed 129B6 background 12 and later confirmed in backcrossed Prnp0/0 mice (C57BL/6NRJ) (Figs. 1A1-2 and B).…”

Section: Introductionmentioning

confidence: 74%

Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrP^Cfor the cytoskeleton

Schmitz

Zafar

Silva

et al. 2014

Prion

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The cellular prion protein (PrP(C)) is a highly conserved protein, which is anchored to the outer surface of the plasma membrane. Even though its physiological function has already been investigated in different cell or mouse models where PrP(C) expression is either upregulated or depleted, its exact physiological role in a mammalian organism remains elusive. Recent studies indicate that PrP(C) has multiple functions and is involved in cognition, learning, anxiety, locomotion, depression, offensive aggression and nest building behavior. While young animals (3 months of age) show only marginal abnormalities, most of the deficits become apparent as the animals age, which might indicate its role in neurodegeneration or neuroprotection. However, the exact biochemical mechanism and signal transduction pathways involving PrP(C) are only gradually becoming clearer. We report the observations made in different studies using different Prnp0/0 mouse models and propose that PrP(C) plays an important role in the regulation of the cytoskeleton and associated proteins. In particular, we showed a nocodazole treatment influenced colocalization of PrP(C) and α tubulin 1. In addition, we confirmed the observed deficits in nest building using a different backcrossed Prnp0/0 mouse line.

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“…Indeed, Collinge et al (1994) showed that Zurich I PrP C -knockout mice had disrupted hippocampal long-term potentiation (LTP), a form of synaptic plasticity involved in memory formation. These mice displayed abnormal behaviour in nest building and novel environment exploration tasks and more pronounced age-related decline in short-term memory compared to wild type controls (Schmitz et al, 2014), effects that are possibly underpinned by impaired LTP. Intriguingly, it has been reported that the effect of ageing on memory can be blocked by infusing wild type mice with a peptide containing the putative PrP C -binding site of STI1 (Rial et al, 2009).…”

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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Loss of Prion Protein Leads to Age-Dependent Behavioral Abnormalities and Changes in Cytoskeletal Protein Expression

Cited by 35 publications

References 53 publications

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrP^Cfor the cytoskeleton

Physiological Functions of the Cellular Prion Protein

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Loss of Prion Protein Leads to Age-Dependent Behavioral Abnormalities and Changes in Cytoskeletal Protein Expression

Cited by 35 publications

References 53 publications

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

The Cellular Prion Protein Controls Notch Signaling in Neural Stem/Progenitor Cells

Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrPCfor the cytoskeleton

Physiological Functions of the Cellular Prion Protein

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Behavioral abnormalities in prion protein knockout mice and the potential relevance of PrP^Cfor the cytoskeleton