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

被引：218

作者：

Ferreira, Diana G. ^{[1
,2
,3
,4
]}

Temido-Ferreira, Mariana ^{[1
]}

Miranda, Hugo Vicente ^{[1
,5
]}

Batalha, Vania L. ^{[1
]}

Coelho, Joana E. ^{[1
]}

Szego, Eva M. ^{[2
]}

Marques-Morgado, Ines ^{[1
]}

Vaz, Sandra H. ^{[1
]}

Rhee, Jeong Seop ^{[6
]}

Schmitz, Matthias ^{[7
,8
]}

Zerr, Inga ^{[7
,8
]}

Lopes, Luisa V. ^{[1
]}

Outeiro, Tiago F. ^{[2
,5
,6
]}

机构：

[1] Univ Lisbon, Fac Med Lisboa, Inst Med Mol, Lisbon, Portugal

[2] Univ Med Ctr Gottingen, Ctr Biostruct Imaging Neurodegenerat, Ctr Nanoscale Microscopy & Mol Physiol Brain, Dept Expt Neurodegenerat, Gottingen, Germany

[3] Univ Porto, Fac Med, Dept Pharmacol & Therapeut, Oporto, Portugal

[4] Univ Porto, MedInUP Ctr Drug Discovery & Innovat Med, Oporto, Portugal

[5] Univ Nova Lisboa, Fac Ciencias Med, NOVA Med Sch, CEDOC,Chron Dis Res Ctr, Lisbon, Portugal

[6] Max Planck Inst Expt Med, Gottingen, Germany

[7] Univ Med Ctr Gottingen, Dept Neurol, Gottingen, Germany

[8] German Ctr Neurodegenerat Dis DZNE Site Gottingen, Gottingen, Germany

来源：

NATURE NEUROSCIENCE | 2017年 / 20卷 / 11期

关键词：

CELLULAR PRION PROTEIN; ADENOSINE A(2A) RECEPTORS; AMYLOID-BETA OLIGOMERS; LONG-TERM POTENTIATION; POSSIBLE KEY MECHANISM; LEWY BODY DISEASES; PARKINSONS-DISEASE; TYROSINE PHOSPHORYLATION; DEPENDENT MECHANISM; CA2+ SIGNALS;

D O I：

10.1038/nn.4648

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

Synucleinopathies, such as Parkinson's disease and dementia with Lewy bodies, are neurodegenerative disorders that are characterized by the accumulation of alpha-synuclein (aSyn) in intracellular inclusions known as Lewy bodies. Prefibrillar soluble aSyn oligomers, rather than larger inclusions, are currently considered to be crucial species underlying synaptic dysfunction. We identified the cellular prion protein (PrPC) as a key mediator in aSyn-induced synaptic impairment. The aSyn-associated impairment of long-term potentiation was blocked in Prnp null mice and rescued following PrPC blockade. We found that extracellular aSyn oligomers formed a complex with PrPC that induced the phosphorylation of Fyn kinase via metabotropic glutamate receptors 5 (mGluR5). aSyn engagement of PrPC and Fyn activated NMDA receptor (NMDAR) and altered calcium homeostasis. Blockade of mGluR5-evoked phosphorylation of NMDAR in aSyn transgenic mice rescued synaptic and cognitive deficits, supporting the hypothesis that a receptor-mediated mechanism, independent of pore formation and membrane leakage, is sufficient to trigger early synaptic damage induced by extracellular aSyn.

引用

页码：1569 / +

页数：14

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