Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2.
An alternative spliced form of the presinilin 2 (PS2) gene (PS2V) lacking exon 5 has previously been reported to be expressed in human brains in sporadic Alzheimer's disease (AD). PS2V encodes the amino-terminal portion of PS2, which contains residues Met1-Leu119 and 5 additional amino acid residues (SSMAG) at its carboxyl terminus. Here we report that PS2V protein impaired the signaling pathway of the unfolded protein response, similarly to familial AD-linked PS1 mutants and caused significant increases in the production of both amyloid beta40 and beta42. Interestingly, PS2V-encoding protein was expressed in neuropathologically affected neurons of the hippocampal CA1 region and temporal cortex in AD patients. These findings suggest that the aberrant splicing of the PS2 gene may be implicated in the neuropathology of sporadic AD.
Sato
N
N
Department of Anatomy, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Imaizumi
K
K
Manabe
T
T
Taniguchi
M
M
Hitomi
J
J
Katayama
T
T
Yoneda
T
T
Morihara
T
T
Yasuda
Y
Y
Takagi
T
T
Kudo
T
T
Tsuda
T
T
Itoyama
Y
Y
Makifuchi
T
T
Fraser
P E
PE
St George-Hyslop
P
P
Tohyama
M
M
D017398:Alternative Splicing; D000544:Alzheimer Disease / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000096:biosynthesis*; D000818:Animals; D001921:Brain / Q000378:metabolism; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053766:Presenilin-2; D015398:Signal Transduction
D016229:Amyloid beta-Peptides; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D053766:Presenilin-2