Truncated presenilin 2 derived from differentially spliced mRNAs does not affect the ratio of amyloid β-peptide 1-42/1-40

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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 Δexon 3,4) or exons 3, 4, and 8 (PS2 Δexon 3,4,8). 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 ∼50% of the PS1 and both PS2 mutations occur within the N-terminal region lacking in the PS2 Δexon3,4 and PS2 Δexon3,4,8 proteins, expression of these truncated proteins does not affect pathological generation of amyloidβ-peptide (Aβ). This suggests that point mutations causing AD are gain of function mutations.

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