An alternative spliced mouse presenilin-2 mRNA encodes a novel gamma-secretase inhibitor.
The gamma-secretase, composed of presenilin-1 (PS1) or presenilin-2 (PS2), nicastrin (NCT), anterior pharynx-defective phenotype 1 (APH-1), and PEN-2, is critical for the development of Alzheimer's disease (AD). PSs are autoproteolytically cleaved, producing an N-terminal fragment (NTF) and a hydrophilic loop domain-containing C-terminal fragment. However, the role of the loop domain in the gamma-secretase complex assembly remains unknown. Here, we report a novel PS2 isoform generated by alternative splicing, named PS2beta, which is composed of an NTF with a hydrophilic loop domain. PS2beta disturbed the interaction between NCT and APH-1, resulting in the inhibition of amyloid-beta production. We concluded that PS2beta may inhibit gamma-secretase activity by affecting the gamma-secretase complex assembly.
Suzuki
Yoshihiro
Y
Department of Neurobiology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194, Japan.
Ohta
Kazunori
K
Itoh
Masanori
M
Sakoh-Sumitomo
Yukari
Y
Mitsuda
Teruhiko
T
Ueda
Masashi
M
Hayakawa-Yano
Yoshika
Y
Li
Shimo
S
Hida
Yoko
Y
Inuzuka
Takashi
T
Jung
Yong-Keun
YK
Nakagawa
Toshiyuki
T
D017398:Alternative Splicing; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D001483:Base Sequence; D003001:Cloning, Molecular; D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D053766:Presenilin-2 / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012689:Sequence Homology, Nucleic Acid
D018076:DNA, Complementary; D004791:Enzyme Inhibitors; D053766:Presenilin-2; D053829:Amyloid Precursor Protein Secretases