Altered binding of mutated presenilin with cytoskeleton-interacting proteins.
The majority of familial Alzheimer's disease (AD) cases are linked to mutations on presenilin 1 and 2 genes (PS1 and PS2). The normal function of the proteins and the mechanisms underlying early-onset AD are currently unknown. To address this, we screened an expression library for proteins that bind differentially to the wild-type PS1 and mutant in the large cytoplasmic loop (PS1L). Thus we isolated the C-terminal tail of the 170 kDa cytoplasmic linker protein (CLIP-170) and Reed-Sternberg cells of Hodgkin's disease-expressed intermediate filament-associated protein (Restin), cytoplasmic proteins linking vesicles to the cytoskeleton. PS1L binding to CLIP-170/restin requires Ca(2+). Treating cells with thapsigargin or ionomycin increased the mutated PS1 in CLIP-170 immunoprecipitates. Further, PS1 and CLIP-170 co-localize in transfected cells and neuronal cultures.
Johnsingh
A A
AA
Department of Psychiatry, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1229, New York, NY 10029, USA.
Johnston
J M
JM
Merz
G
G
Xu
J
J
Kotula
L
L
Jacobsen
J S
JS
Tezapsidis
N
N
D000544:Alzheimer Disease / Q000378:metabolism; D017124:Conserved Sequence; D003599:Cytoskeleton / Q000378:metabolism*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D015759:Ionomycin / Q000494:pharmacology; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008869:Microtubule-Associated Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D009154:Mutation; D009363:Neoplasm Proteins / Q000737:chemistry* / Q000235:genetics / Q000302:isolation & purification; D019151:Peptide Library; D011233:Precipitin Tests; D053764:Presenilin-1; D016539:Reed-Sternberg Cells / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology
D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; C508853:PSEN1 protein, human; D019151:Peptide Library; D053764:Presenilin-1; C076744:cytoplasmic linker protein 170; D015759:Ionomycin; D019284:Thapsigargin