α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

Ferreira, Diana G.; Temido‐Ferreira, Mariana; Miranda, Hugo Vicente; Batalha, Vânia L.; Coelho, Joana; Szegő, Éva M.; Marques-Morgado, Inês; Vaz, Sandra H.; Rhee, Jeong Seop; Schmitz, Matthias; Zerr, Inga; Lopes, Luı́sa V.; Outeiro, Tiago F.

doi:10.1038/nn.4648

Cited by 231 publications

(315 citation statements)

References 61 publications

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“…The interaction of αSyn oligomers with PrP C induces the phosphorylation of Fyn kinase via mGluR5 and the consequent phosphorylation of the NMDAR2B. In addition, we found that this interaction triggers a signaling cascade that leads to synaptic dysfunction in the hippocampus . Interestingly, similar effects were reported on the interaction of Aβ with PrP C in the context of Alzheimer's disease (AD) …”

Section: Mechanisms Of Toxicity: From Pores To Signaling Cascadessupporting

confidence: 70%

“…Recently, we found that the interaction of αSyn oligomers with PrP C induces the phosphorylation of Fyn kinase via metabotropic glutamate receptor 5 (mGluR5), and the consequent phosphorylation of the N‐methyl‐ d ‐aspartate receptor 2B subunit (NMDAR2B). In addition, we found that this interaction triggers a signaling cascade that leads to synaptic dysfunction, demonstrating the important role of PrP C in αSyn pathology. In this perspective, we briefly describe the putative cellular mechanisms involved in the spreading of αSyn pathology and focus on membrane proteins that act as sensors for αSyn.…”

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confidence: 74%

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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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Section: Mechanisms Of Toxicity: From Pores To Signaling Cascadessupporting

confidence: 70%

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confidence: 74%

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

2018

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“…[51] In addition, recent studies show that the production of reactive oxygen species (ROS) and neuronal toxicity induced by a-synuclein (aSyn) aggregates is entirely dependent on the presence of both copper and iron, and the effect is completely blocked by specific chelators of the two metal ions. [70] In fact, it has been shown that DA promotes PrP aggregation, probably through the effect of DAQ/ROSspecies, [71] and it is likely that similar reactions will affect Ab.I na ddition, both Ab [72] and aSyn [73] interact with PrP,inducing cognitive impairment, and metal ions may well be involved in these interactions. [68] In the redox processes promoted by metal ions on DA,avariety of potentially toxic species such as DASQ,D AQ,O 2 À ,H 2 O 2 , and hydroxyl radical can be formed through an intricate chain of reactions.…”

Section: Metal-catalyzed Dopamine Oxidationmentioning

confidence: 99%

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

et al. 2019

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Dopamine (DA) is the most important catecholamine in the brain, as it is the most abundant and the precursor of other neurotransmitters. Degeneration of nigrostriatal neurons of substantia nigra pars compacta in Parkinson's disease represents the best‐studied link between DA neurotransmission and neuropathology. Catecholamines are reactive molecules that are handled through complex control and transport systems. Under normal conditions, small amounts of cytosolic DA are converted to neuromelanin in a stepwise process involving melanization of peptides and proteins. However, excessive cytosolic or extraneuronal DA can give rise to nonselective protein modifications. These reactions involve DA oxidation to quinone species and depend on the presence of redox‐active transition metal ions such as iron and copper. Other oxidized DA metabolites likely participate in post‐translational protein modification. Thus, protein–quinone modification is a heterogeneous process involving multiple DA‐derived residues that produce structural and conformational changes of proteins and can lead to aggregation and inactivation of the modified proteins.

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“…However, Ab oligomer is also reported to induce calcium influx into neuronal cells and interestingly even low picomolar concentration of the oligomers comparable to the concentration of species detected in CSF, induces calcium influx [65]. Notably, a-syn oligomers and Ab oligomers have also been reported to trigger calcium deregulation through receptor -mediated mechanisms, involving an interaction between the oligomer complex and PrP c [67,68]. Notably, a-syn oligomers and Ab oligomers have also been reported to trigger calcium deregulation through receptor -mediated mechanisms, involving an interaction between the oligomer complex and PrP c [67,68].…”

Section: Membrane Disruption and Calcium Dysregulationmentioning

confidence: 99%

Crucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases

2018

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Misfolding and aggregation of the proteins amyloid-β, tau and alpha-synuclein is the predominant pathology underlying the neurodegenerative disorders, Alzheimer's and Parkinson's disease. While end stage insoluble products of aggregation have been well characterised in human and animal models of disease, accumulating evidence from biophysical, cellular and in vivo studies has shown that soluble intermediates of aggregation, or oligomers, may be the key species that mediate toxicity and underlie seeding and spreading in disease. Here, we review the process of protein misfolding, and the intrinsic and extrinsic processes that cause the native states of the key aggregating proteins to undergo conformational change to form oligomers and ultimately fibrils. We discuss the structural features of the key toxic intermediate, and describe the putative mechanisms by which oligomers may cause cell toxicity. Finally, we explore the potential therapeutic approaches raised by the oligomer hypothesis in neurodegenerative disease.

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α-synuclein interacts with PrPC to induce cognitive impairment through mGluR5 and NMDAR2B

Cited by 231 publications

References 61 publications

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

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

Dopamine, Oxidative Stress and Protein–Quinone Modifications in Parkinson's and Other Neurodegenerative Diseases

Crucial role of protein oligomerization in the pathogenesis of Alzheimer's and Parkinson's diseases

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