Analysis of alteration of p75NTR processing and signalling by PS2 mutation and gamma-secretase inhibition.
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 gamma-secretase complex responsible for proteolytic processing of type I membrane proteins. p75NTR, a common neurotrophin receptor, was shown to be subject to gamma-secretase processing. However, it is not clear if the p75NTR downstream signal is altered in response to gamma-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 gamma-secretase inhibition in SHSY-5Y cells. The activity of the small GTPase RhoA is strongly affected by these treatments. This study demonstrates that gamma-secretase and PS2 play an important role in regulating neurotrophin signal transduction and either mutation of PS2 or inhibition of gamma-secretase disturbs this function.
Ito
Yoshio
Y
Department of Geriatric Medicine, Queen's University Belfast, Whitla Medical Building, 97 Lisburn Road, Belfast, BT9 7BL, Northern Ireland.
Ishii
Azusa
A
Passmore
A Peter
AP
McIlroy
Stephen P
SP
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D006801:Humans; D015151:Immunoblotting; D009154:Mutation; D053766:Presenilin-2 / Q000235:genetics*; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D053449:TNF Receptor-Associated Factor 4 / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
D053766:Presenilin-2; D020800:Receptor, Nerve Growth Factor; D053449:TNF Receptor-Associated Factor 4; C506367:TRAF4 protein, human; D053829:Amyloid Precursor Protein Secretases; D020742:rhoA GTP-Binding Protein