Overcoming barriers and thresholds – signaling of oligomeric Aβ through the prion protein to Fyn

Molecular Neurodegeneration

Gerold Schmitt-Ulms²  C Geeth Gunawardana¹  Carl He Ren²  Hansen Wang¹ 

[1] Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Tanz Neuroscience Building, 6 Queen’s Park Crescent West, Toronto, Ontario M5S 3H2, Canada;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S1A8, Canada

关键词: Excitotoxicity;    Tau;    Prion protein;    Fyn;    Amyloid β peptide;    Alzheimer disease;   

Others  :  862255
DOI  :  10.1186/1750-1326-8-24

 received in 2013-05-17, accepted in 2013-07-09,  发布年份 2013

【 摘 要 】

Evidence has been mounting for an involvement of the prion protein (PrP) in a molecular pathway assumed to play a critical role in the etiology of Alzheimer disease. A currently popular model sees oligomeric amyloid β (oAβ) peptides bind directly to PrP to emanate a signal that causes activation of the cytoplasmic tyrosine kinase Fyn, an essential player in a cascade of events that ultimately leads to NMDA receptor-mediated excitotoxicity and hyper-phosphorylation of tau. The model does not reveal, however, how extracellular binding of oAβ to PrP is communicated across the plasma membrane barrier to affect activation of Fyn. A scenario whereby PrP may adapt a transmembrane topology to affect Fyn activation in the absence of additional partners is currently not supported by evidence. A survey of known candidate PrP interactors leads to a small number of molecules that are known to acquire a transmembrane topology and understood to contribute to Fyn activation. Because multiple signaling pathways converge onto Fyn, a realistic model needs to take into account a reality of Fyn acting as a hub that integrates signals from multiple inhibitory and activating effectors. To clarify the role of PrP in oAβ-dependent excitotoxicity, future studies may need to incorporate experimental designs that can probe the contributions of Fyn modulator pathways and rely on analogous readouts, rather than threshold effects, known to underlie excitotoxic signaling.

【 授权许可】

   
2013 Wang et al.; licensee BioMed Central Ltd.

【 图 表 】

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