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Truncated presenilin 2 derived from differentially spliced mRNA does not affect the ratio of amyloid beta-peptide
J Grünberg1, J Walter, C Eckman
1Central Institute of Mental Health, Department of Molecular Biology, Mannheim, Germany.
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.
Insights
Familial Alzheimer's disease (FAD) is linked to presenilin (PS) mutations. Truncated PS2 proteins, lacking N-terminal regions, regulate PS fragments but do not impact amyloid beta-peptide generation, suggesting gain-of-function mutations.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Familial Alzheimer's disease (FAD) is primarily caused by mutations in presenilin (PS) genes.
- Presenilin proteins are crucial components of the gamma-secretase complex involved in amyloid precursor protein (APP) processing.
Purpose of the Study:
- To characterize the expression and function of two alternative PS2 transcripts (PS2 deltaexon3,4 and PS2 deltaexon3,4,8) lacking specific exons.
- To investigate the impact of these N-terminally truncated PS2 proteins on endogenous PS fragment formation and amyloid beta-peptide (Abeta) generation.
Main Methods:
- Analysis of alternative splicing in PS2 gene transcripts.
- Expression and translation studies of truncated PS2 variants.
- Assessment of PS fragment regulation and Abeta production in cellular models.
Main Results:
- Two naturally occurring alternative PS2 transcripts, PS2 deltaexon3,4 and PS2 deltaexon3,4,8, were identified, lacking N-terminal coding regions.
- These transcripts are translated into N-terminally truncated PS2 proteins.
- The C-terminal half of PS2 is sufficient for regulating endogenous PS fragment formation.
- Expression of these truncated PS2 proteins did not alter pathological Abeta generation, despite mutations often occurring in the N-terminal region.
Conclusions:
- The C-terminal domain of PS2 is functionally relevant for regulating PS fragments.
- The lack of impact on Abeta generation by truncated PS2 proteins suggests that FAD-associated point mutations are likely gain-of-function mutations rather than loss-of-function.