Role of prions in neuroprotection and neurodegeneration

Zamponi, Gerald W.; Stys, Peter K.

doi:10.4161/pri.3.4.9549

Cited by 14 publications

(8 citation statements)

References 39 publications

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“…Even the evidence of preclinical downregulation of PrP C in several disease models was discussed basically as a possible neuroprotective event, on the grounds that it would provide less substrate for conformational conversion and thus for disease progress (Mays et al, 2014 ). In fact, gain- and loss-of-function components are not mutually exclusive, and the abundant evidence for neuroprotective effects of PrP C (Zamponi and Stys, 2009 ; Martins et al, 2010 ; Biasini et al, 2012 ; Onodera et al, 2014 ; Zeng et al, 2015 ) concurs with the hypothesis that the early and robust loss of PrP C may be involved in the pathogenesis of TSEs. In turn, whereas PrP C has been identified as a pathogenic receptor for AβO in models of AD, binding of the prion protein to hop/STI1 also mediates neuroprotection against AβO neurotoxicity (Ostapchenko et al, 2013 ), which reinforce the interest in physiological properties of PrP C .…”

Section: Corruption Of Prion Protein-mediated Signaling and The Scaffmentioning

confidence: 77%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

111

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Section: Corruption Of Prion Protein-mediated Signaling and The Scaffmentioning

confidence: 77%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

111

104

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“…It is becoming increasingly clear that cellular prion protein is an important neuromodulator [37], but there have been few studies showing its possible role in mood disorders. Our data demonstrate that the PrP −/− mice exhibit an increase in immobility time compared to wild-type mice in both the FST and in the TST.…”

Section: Discussionmentioning

confidence: 99%

Depressive-like behaviour of mice lacking cellular prion protein

Gadotti

Bonfield

Zamponi

2012

Behavioural Brain Research

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Cellular Prion Protein (PrP(C)) is known to mediate a protective role in several neurological conditions such as ischemia and epilepsy. However, so far, little information is available concerning the role of PrP(C) in psychiatric disorders such as depression. Here, we have used PrP(C) null mice to examine a putative role of PrP(C) in depressive-like states. Prion protein null mice exhibited depressive-like behaviour when compared to wild-type mice in both the Forced Swimming Test (FST) and Tail Suspension Test (TST). The clinical antidepressant drug imipramine and the NMDA receptor antagonist MK-801 reversed the depressive-like behaviour observed for knockout mice in the TST. The present data thus indicate that PrP(C) exerts a critical role in modulating the depressive-like state in mice, reinforcing the notion that PrP(C) might be associated with alterations in mood disorder states, and suggests a possible role of PrP(C) as a potential drug target for treating depressive disorders.

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“…This abnormal protein accumulates in the brain, forming polymeric aggregates that disrupt synapses, leading to loss of dendrites and finally neuronal death (Soto and Satani, 2011 ). Although this pathological role of misfolded PrP C has been established and studied extensively, the function of PrP C in the normal brain remains largely unknown (Linden et al, 2008 ; Zamponi and Stys, 2009 ; Stys et al, 2012 ; Black et al, 2014 ). Initial studies with PrP-null mice revealed a mild pathology, such as a slight impairment of spatial learning (Collinge et al, 1994 ; Manson et al, 1995 ), but otherwise normal development (Büeler et al, 1992 ; Manson et al, 1994 ; Criado et al, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP−/− Mice

Fan

Stemkowski

Gandini

et al. 2016

Front. Cell. Neurosci.

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Genetic ablation of cellular prion protein (PrPC) has been linked to increased neuronal excitability and synaptic activity in the hippocampus. We have previously shown that synaptic activity in hippocampi of PrP-null mice is increased due to enhanced N-methyl-D-aspartate receptor (NMDAR) function. Here, we focused on the effect of PRNP gene knock-out (KO) on intrinsic neuronal excitability, and in particular, the underlying ionic mechanism in hippocampal neurons cultured from P0 mouse pups. We found that the absence of PrPC profoundly affected the firing properties of cultured hippocampal neurons in the presence of synaptic blockers. The membrane impedance was greater in PrP-null neurons, and this difference was abolished by the hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker ZD7288 (100 μM). HCN channel activity appeared to be functionally regulated by PrPC. The amplitude of voltage sag, a characteristic of activating HCN channel current (Ih), was decreased in null mice. Moreover, Ih peak current was reduced, along with a hyperpolarizing shift in activation gating and slower kinetics. However, neither HCN1 nor HCN2 formed a biochemical complex with PrPC. These results suggest that the absence of PrP downregulates the activity of HCN channels through activation of a cell signaling pathway rather than through direct interactions. This in turn contributes to an increase in membrane impedance to potentiate neuronal excitability.

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Role of prions in neuroprotection and neurodegeneration

Cited by 14 publications

References 39 publications

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Depressive-like behaviour of mice lacking cellular prion protein

Reduced Hyperpolarization-Activated Current Contributes to Enhanced Intrinsic Excitability in Cultured Hippocampal Neurons from PrP−/− Mice

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