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.
Mesh Terms:
Alternative Splicing, Amyloid Precursor Protein Secretases, Animals, Base Sequence, Cloning, Molecular, DNA, Complementary, Enzyme Inhibitors, Humans, Mice, Molecular Sequence Data, Presenilin-2, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Nucleic Acid
Alternative Splicing, Amyloid Precursor Protein Secretases, Animals, Base Sequence, Cloning, Molecular, DNA, Complementary, Enzyme Inhibitors, Humans, Mice, Molecular Sequence Data, Presenilin-2, Reverse Transcriptase Polymerase Chain Reaction, Sequence Homology, Nucleic Acid
FEBS Lett.
Date: May. 06, 2009
PubMed ID: 19376115
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