The L392V mutation of presenilin 1 associated with autosomal dominant early-onset Alzheimer's disease alters the secondary structure of the hydrophilic loop

AUTOSOMAL dominant early-onset Alzheimer's disease results:mainly from muta tions of the presenilin 1 (PSEN1), gene, which codes for an integral membra ne protein of 467 amino acids. The hydrophilic loop (amino acids;263-407) o f PSEN1, in which many pathogenic mutations have been localized, appears to be crucial for the protein function since it includes the binding domains- to different PSEN1 partners. Using circular dichroism (CD) we analyzed the structural effects of the pathogenic L392V mutation and compared them with those of the E318G substitution. This study revealed that, the L392V mutati on, in a phospholipidic medium which mimics the in vivo membrane environmen t, reduces the alpha helix content of the PSEN1 loop, whereas the E318G sub stitution, considered as a polymorphism,: does not. These results suggest t hat the pathogenic effect of some PSEN1 mutations within the hydrophilic lo op could be the alteration of the interaction to the different binding prot eins through a disruption of the secondary structure. (C) 1999 Lippincott W illiams & Wilkins.