Alzheimer's presenilin 1 is a putative membrane receptor for rab GDP dissociation inhibitor.
Mutations in the presenilin 1 ( PS-1 ) gene cause Alzheimer's disease (AD). These mutations alter the processing of the amyloid precursor protein (APP) by increasing the production of the fibrillogenic amyloid fragment, Abeta1-42/43. Since the secretase activities that process APP are localized in different intracellular compartments, it is likely that membrane transport is a key factor in the pathogenesis of AD. In this report we provide evidence for a direct connection between PS-1 and membrane transport. We show that the N-terminus of PS-1 binds to rab GDP dissociation inhibitor (rabGDI), a regulatory factor in vesicle transport. In PS-1-deficient neurons we found a 2-fold decrease in the amount of rabGDI associated with membranes. Our findings are compatible with PS-1 being a membrane receptor for rabGDI. This is in line with a role of PS-1 in the regulation of protein trafficking in the ER/Golgi, which can modulate the production of Abeta.
Scheper
W
W
Laboratory Neurozintuigen and Department of Neurology, Academic Medical Center, PO Box 22700, 1105 AZ Amsterdam, The Netherlands.
Zwart
R
R
van der Sluijs
P
P
Annaert
W
W
Gool
W A
WA
Baas
F
F
D000328:Adult; D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D001693:Biological Transport, Active / Q000235:genetics; D002451:Cell Compartmentation / Q000235:genetics; D002460:Cell Line; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
C086796:GDP dissociation inhibitor 1; D020730:Guanine Nucleotide Dissociation Inhibitors; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011956:Receptors, Cell Surface