Effects of PS1 deficiency on membrane protein trafficking in neurons.
We have examined the trafficking and metabolism of the beta-amyloid precursor protein (APP), an APP homolog (APLP1), and TrkB in neurons that lack PS1. We report that PS1-deficient neurons fail to secrete Abeta, and that the rate of appearance of soluble APP derivatives in the conditioned medium is increased. Remarkably, carboxyl-terminal fragments (CTFs) derived from APP and APLP1 accumulate in PS1-deficient neurons. Hence, PS1 plays a role in promoting intramembrane cleavage and/or degradation of membrane-bound CTFs. Moreover, the maturation of TrkB and BDNF-inducible TrkB autophosphorylation is severely compromised in neurons lacking PS1. We conclude that PS1 plays an essential role in modulating trafficking and metabolism of a selected set of membrane and secretory proteins in neurons.
Naruse
S
S
Department of Pharmacological and Physiological Sciences, The University of Chicago, Illinois 60637, USA.
Thinakaran
G
G
Luo
J J
JJ
Kusiak
J W
JW
Tomita
T
T
Iwatsubo
T
T
Qian
X
X
Ginty
D D
DD
Price
D L
DL
Borchelt
D R
DR
Wong
P C
PC
Sisodia
S S
SS
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D005333:Fetus; D008565:Membrane Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D053764:Presenilin-1
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; D053764:Presenilin-1