title: Truncated presenilin 2 derived from differentially spliced mRNA does not affect the ratio of amyloid beta-peptide 1-42/1-40.
abstract: Numerous mutations in the presenilin (PS) genes cause early onset familial Alzheimer's disease (FAD). Here we characterize the expression of two naturally occurring alternative PS2 transcripts which lack either exons 3 and 4 (PS2 deltaexon3,4) or exons 3, 4, and 8 (PS2 deltaexon3,4,8). These transcripts do not contain the natural initiation codon within exon 3. The transcripts are efficiently translated as N-terminal truncated proteins. These deleted proteins are still able to regulate formation of endogenous PS fragments, indicating that the C-terminal half of the PS2 protein is sufficient for this phenomenon. Although approximately 50% of the PS1 and both PS2 mutations occur within the N-terminal region lacking in the PS2 deltaexon3,4 and PS2 deltaexon3,4,8 proteins, expression of these truncated proteins does not affect pathological generation of amyloid beta-peptide (Abeta). This suggests that point mutations causing AD are gain of function mutations.
authors.affiliation: Central Institute of Mental Health, Department of Molecular Biology, Mannheim, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Grünberg
authors.forename: J
authors.initials: J
authors.lastname: Walter
authors.forename: C
authors.initials: C
authors.lastname: Eckman
authors.forename: A
authors.initials: A
authors.lastname: Capell
authors.forename: A
authors.initials: A
authors.lastname: Schindzielorz
authors.forename: S
authors.initials: S
authors.lastname: Younkin
authors.forename: N
authors.initials: N
authors.lastname: Mehta
authors.forename: J
authors.initials: J
authors.lastname: Hardy
authors.forename: C
authors.initials: C
authors.lastname: Haass
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000032:analysis / Q000235:genetics*; D000818:Animals; D019556:COS Cells; D015342:DNA Probes; D005091:Exons; D006801:Humans; D007668:Kidney / Q000166:cytology; D008565:Membrane Proteins / Q000032:analysis / Q000235:genetics*; D010446:Peptide Fragments / Q000032:analysis / Q000235:genetics*; D053766:Presenilin-2; D014176:Protein Biosynthesis / Q000502:physiology; D012326:RNA Splicing / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D013347:Subcellular Fractions / Q000737:chemistry
chemical_list: D016229:Amyloid beta-Peptides; D015342:DNA Probes; D008565:Membrane Proteins; C508861:PSEN2 protein, human; D010446:Peptide Fragments; D053766:Presenilin-2; D012333:RNA, Messenger; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)