Analysis of alteration of p75NTR processing and signalling by PS2 mutation and γ-secretase inhibition

• Published in: Neurobiology of disease Vol. 27; no. 3; pp. 258 - 264
• Main Authors: Ito, Yoshio, Ishii, Azusa, Passmore, A. Peter, McIlroy, Stephen P
• Format: Journal Article
• Language: English
• Published: United States Elsevier 01.09.2007
• Subjects: Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Cell Line, Tumor; Humans; Immunoblotting; Mutation; Neurology; Neurotrophin pathway; p75NTR; Presenilin; Presenilin-2 - genetics; Receptor, Nerve Growth Factor - metabolism; RhoA; rhoA GTP-Binding Protein - metabolism; Signal Transduction - physiology; TNF Receptor-Associated Factor 4 - metabolism; TrkA; Presenilin; TrkA; Alzheimer’s disease; Neurotrophin pathway; p75 NTR; RhoA
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2007.05.002

Abstract The presenilins (PSs) were identified as causative genes in cases of early-onset familial Alzheimer’s disease (AD) and current evidence indicates that PSs are part of the γ-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR , a common neurotrophin receptor, was shown to be subject to γ-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to γ-secretase cleavage, and further there is a possibility that AD-related PS mutations may affect this cleavage, resulting in pathogenic alterations in signal transduction. In this study, we confirmed that p75NTR downstream signalling is altered by PS2 mutation or γ-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that γ-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of γ-secretase disturbs this function.