Presenilin 1 is required for maturation and cell surface accumulation of nicastrin.
Proteolytic processing of amyloid precursor protein generates beta-amyloid (Abeta) peptides that are deposited in senile plaques in brains of aged individuals and patients with Alzheimer's disease. Presenilins (PS1 and PS2) facilitate the final step in Abeta production, the intramembranous gamma-secretase cleavage of amyloid precursor protein. Biochemical and pharmacological evidence support a catalytic or accessory role for PS1 in gamma-secretase cleavage, as well as a regulatory role in select membrane protein trafficking. In this report, we demonstrate that PS1 is required for maturation and cell surface accumulation of nicastrin, an integral component of the multimeric gamma-secretase complex. Using kinetic labeling studies we show that in PS1(-/-)/PS2(-/-) cells nicastrin fails to reach the medial Golgi compartment, and as a consequence, is incompletely glycosylated. Stable expression of human PS1 restores these deficiencies in PS1(-/-) fibroblasts. Moreover, membrane fractionation studies show co-localization of PS1 fragments with mature nicastrin. These results indicate a novel chaperone-type role for PS1 and PS2 in facilitating nicastrin maturation and transport in the early biosynthetic compartments. Our findings are consistent with PS1 influencing gamma-secretase processing at multiple steps, including maturation and intracellular trafficking of substrates and component(s) of the gamma-secretase complex.
Leem
Jae Yoon
JY
Department of Neurobiology, Committee on Neurobiology, The University of Chicago, Chicago, Illinois 60637, USA.
Vijayan
Shrijay
S
Han
Ping
P
Cai
Dongming
D
Machura
Michael
M
Lopes
Kryslaine O
KO
Veselits
Margaret L
ML
Xu
Huaxi
H
Thinakaran
Gopal
G
D053829:Amyloid Precursor Protein Secretases; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D002462:Cell Membrane / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D053764:Presenilin-1; D021381:Protein Transport; D013347:Subcellular Fractions / Q000378:metabolism; D014407:Tumor Cells, Cultured
D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; C413604:nicastrin protein; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse