Altered binding of mutated presenilin with cytoskeleton-interacting proteins

The majority of familial Alzheimer's disease (AD) cases are linked to mutat ions 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 lo op (PS1L). Thus,ve isolated the C-terminal tail of the 170 kDa cytoplasmic linker protein (CLIP-170) and Reed-Sternberg cells of Hodgkin's disease-exp ressed intermediate filament-associated protein (Restin), cytoplasmic prote ins linking vesicles to the cytoskeleton, PS1L binding to CLIP-170/restin r equires Ca2+. Treating cells with thapsigargin or ionomycin increased the m utated PS1 in CLIP-170 immunoprecipitates. Further, PSI and CLIP-170 co-loc alize in transfected cells and neuronal cultures. (C) 2000 Federation of Eu ropean Biochemical Societies.