Involvement of Cellular Prion Protein in α-Synuclein Transport in Neurons

Urrea, Laura; Segura-Feliu, Miriam; Masuda-Suzukake, Masami; Hervera, Arnau; Pedraz, Lucas; Aznar, José Manuel García; Vila, Miquel; Samitier, J.; Torrents, Eduard; Ferrer, Isidró; Gavı́n, Rosalina; Hagesawa, Masato; Rı́o, José Antonio del

doi:10.1007/s12035-017-0451-4

Cited by 63 publications

(77 citation statements)

References 70 publications

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“…A number of reports claim that the role of the cellular prion protein in neurodegeneration is not limited to prion disorders, but extends also to the pathogenesis of Alzheimer's disease and synucleinopathies (16,17,20,23,36). Indeed, several reports indicate that PrP C mediates the neurotoxicity of several protein aggregates (a-synuclein, amyloid b) in two different ways.…”

Section: Discussionmentioning

confidence: 99%

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

Cecco

Celauro

Vanni

et al. 2020

Preprint

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AbstractTauopathies are prevalent, invariably fatal brain diseases for which no cure is available. Tauopathies progressively affect the brain through cell-to-cell transfer of tau protein amyloids, yet the spreading mechanisms are unknown. Here we show that the cellular prion protein (PrPC) facilitates the uptake of tau aggregates by cultured cells, possibly by acting as an endocytic receptor. In mouse neuroblastoma cells, we found that tau amyloids bind to PrPC; internalization of tau fibrils was reduced in isogenic cells devoid of the gene encoding PrPC. Antibodies against N-proximal epitopes of PrPC impaired the binding of tau amyloids and decreased their uptake. Surprisingly, exposure of chronically prion-infected cells to tau amyloids reduced the accumulation of aggregated prion protein; this effect lasted for more than 72 hours after amyloid removal. These results point to bidirectional interactions between the two proteins: whilst PrPC mediates the entrance of tau fibrils in cells, PrPSc buildup is greatly reduced in their presence, possibly because of an impairment in the prion conversion process.

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Section: Discussionmentioning

confidence: 99%

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

Cecco

Celauro

Vanni

et al. 2020

Preprint

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“…Previous studies found that the spreading of αSyn can occur in the absence of PrP C , suggesting it is not required for the transport of αSyn. However, this transport is faster in the presence of PrP C …”

Section: Prpc As a Mediator Of The Spreading Of αSynmentioning

confidence: 96%

“…More recently, PrP C was identified as a possible sensor for αSyn aggregates . In addition to interacting with αSyn and amyloid‐β (Aβ), it was recently proposed that PrP C might act as a conformation‐specific sensor for disease‐associated proteins, suggesting a more general role in the pathogenesis of various neurodegenerative diseases .…”

Section: Different Cell Surface Proteins Mediate the Internalization mentioning

confidence: 99%

Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

2018

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Parkinson's disease and other synucleinopathies are characterized by the accumulation of aggregated α‐synuclein in intracellular proteinaceous inclusions. The progressive nature of synucleinopathies seems to be related to the cell‐to‐cell spreading of α‐synuclein pathology, and several possible mechanisms have been put forward to explain this phenomenon. In our recent study, we found that α‐synuclein oligomers interact with cellular prion protein in glutamatergic synapses. This interaction triggered a signaling cascade involving phosphorylation of Fyn kinase and activation of the N‐methyl‐d‐aspartate receptor, thereby leading to synaptic dysfunction. Here, we present relevant plasma membrane proteins that have been described to interact with α‐synuclein and discuss the possible pathological implications. We focus primarily on the prion protein and propose a pathological mechanism in which the interaction between α‐synuclein and prion protein leads to the formation of cofilin/actin rods, culminating in long‐term potentiation impairment and cognitive dysfunction. We posit that deciphering the mechanisms involved in sensing specific forms of extracellular α‐synuclein and transducing this information may prove invaluable in our quest to devise novel diagnostic and therapeutic approaches in PD and other synucleinopathies. © 2018 International Parkinson and Movement Disorder Society

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“…Indeed, recombinant -synuclein fibrils spread among neurons in wild-type mice (Luk et al, 2012;Masuda-Suzukake et al, 2014;Urrea et al, 2017). Intranigral or intrastriatal inoculation of PD-derived LB extracts in monkeys results in progressive nigrostriatal neurodegeneration (Recasens et al, 2014).…”

Section: In Vivo Studiesmentioning

confidence: 99%

“…From these results, several laboratories started to analyse whether PrP C might also be a cellular partner of other PS (Resenberger et al, 2011a), and whether PrP C may participate in or regulate the spreading of particular misfolded aggregates and associated neuropathologies. Recent results suggest that membrane-anchored PrP C may also bind to -synuclein (Aulic et al, 2017;Ferreira et al, 2017;Urrea et al, 2017) and may participate in its neuronal spreading (Aulic et al, 2017;Urrea et al, 2017). In this review, we discuss neuronal cell surface molecules with high affinity for disease-associated PS, particularly -amyloid and -synuclein, with a focus on the role of PrP C in this process.…”

Section: Introductionmentioning

confidence: 99%

Role of cellular prion protein in interneuronal amyloid transmission

Rı́o

Ferrer

Gavı́n

2018

Progress in Neurobiology

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Several studies have indicated that certain misfolded amyloids composed of tau, β-amyloid or α-synuclein can be transferred from cell to cell, suggesting the contribution of mechanisms reminiscent of those by which infective prions spread through the brain. This process of a 'prion-like' spreading between cells is also relevant as a novel putative therapeutic target that could block the spreading of proteinaceous aggregates throughout the brain which may underlie the progressive nature of neurodegenerative diseases. The relevance of β-amyloid oligomers and cellular prion protein (PrP) binding has been a focus of interest in Alzheimer's disease (AD). At the molecular level, β-amyloid/PrP interaction takes place in two differently charged clusters of PrP. In addition to β-amyloid, participation of PrP in α-synuclein binding and brain spreading also appears to be relevant in α-synucleopathies. This review summarizes current knowledge about PrP as a putative receptor for amyloid proteins and the physiological consequences of these interactions.

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Involvement of Cellular Prion Protein in α-Synuclein Transport in Neurons

Cited by 63 publications

References 70 publications

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

The uptake of tau amyloid fibrils is facilitated by the cellular prion protein and hampers prion propagation in cultured cells

Sensing α‐Synuclein From the Outside via the Prion Protein: Implications for Neurodegeneration

Role of cellular prion protein in interneuronal amyloid transmission

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