. Alternative splicing in a presenilin 2 variant associated with Alzheimer disease. Ann Clin Transl Neurol. 2019 Apr;6(4):762-777. Epub 2019 Mar 10 PubMed.


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  1. Although I am a minor co-author on this paper, I would, nevertheless, like to comment on it to point out how very significant I think it is.

    In 2016 I published, with others, a review on the role of the presenilin genes in early onset familial AD (Jayne et al., 2016). In it we pointed to an apparent “rule” governing fAD-like mutations in the PSENs. We described how every one of the more than 220 PSEN mutations then accepted as causing fAD always produces a transcript with an open reading frame that includes the original stop codon. The fAD mutations can be deletions, insertions, missense mutations, and even those causing some degree of aberrant transcript splicing. However, there will always be a transcript produced that is “full-length” in that it includes C-terminal PSEN-coding sequences. We described this as the “reading frame preservation rule.”

    The importance of this rule is illustrated by two facts.

    1) “Null” mutations that, e.g., truncate the PSEN open reading frame have never been found to cause fAD. This despite the fact that nonsense and frameshift mutations are quite common forms of mutation for genes in which reduced function causes disease. For example, in the 2012 study of possible fAD mutations in SORL1 by Pottier et al. (2012), two of seven mutations are nonsense mutations, supporting the possibility that decreased SORL1 function promotes AD.

    2) The P242Lfs*11 frameshift mutation of PSEN1 does truncate the open reading frame but does not appear to cause fAD (Wang et al., 2010). Instead it causes an entirely different disease, hidradenitis suppurativa (familial acne inversa), as do mutations in other components of the γ-secretase complex (Wang et al., 2010). These two observations strongly support that fAD mutations in the PSENs are pathogenic by a gain-of-function mechanism. This, together with other data, led us to propose that fAD mutations in the PSENs cause neurodegeneration via an effect on PSEN holoprotein function rather than on the γ-secretase activity formed after endoproteolysis of the holoprotein (Jayne et al., 2016). 

    However, there was a fly in the ointment for this model, i.e. the K115Efs*11 mutation of PSEN2 first described by Jayadev et al. in 2010. This frameshift causes truncation of the open reading frame near the end of exon 5. Interestingly, the putative truncated protein that would be encoded by transcripts containing this mutation would resemble a naturally occurring isoform of PSEN2, “PS2V,” that is formed when hypoxia/oxidative stress causes an alternative splicing event that excludes exon 6 from transcripts (thus altering the reading frame and leading to an earlier stop codon in exon 7 sequence) (Sato et al., 1999). Since PS2V levels are increased in late onset AD brains (Sato et al., 1999Smith et al., 2004), and this isoform is known to inhibit the unfolded protein response (Sato et al., 2001Moussavi et al., 2015), we had previously suggested that the K115Efs*11 mutation of PSEN2 might promote early onset AD through forced expression of a PS2V mimic (Moussavi et al., 2015). Nevertheless, K115Efs*11 was the sole exception to the reading frame preservation rule and so remained as an incongruous fact.

    Now the Braggin et al. paper shows that K115Efs*11 is, instead, “the exception that proves the rule.” The two-nucleotide deletion of K115Efs can, in fact, induce production of two forms of “full-length” open reading frame transcript. If exon 6 of PSEN2 is excluded from transcripts to form PS2V, then, when exon 5 sequence is ligated to exon 7 sequence, the open reading frame is reinstated rather than being truncated, but with significant changes to sequence normally coding for the first lumenal loop of the PSEN2 protein. Even more remarkably, a novel alternative splice form was discovered that incorporates 77 nucleotides from intron 5. While this normally shifts the reading frame, in the presence of the K115fs mutation the original reading frame is reinstated so that an additional 25 codons are added in the region coding for the first lumenal loop of the protein.

    The reading frame preservation rule is thus absolute for the hundreds of mutations collectively in PSEN1 and PSEN2 that cause early onset fAD. As a phenomenon, it is far more consistent than vague (Tang and Kepp, 2019) and possibly nonexistent (Sun et al., 2017) correlations between Aβ40/42 ratios and disease onset ages, which may, in any case, be explained by oxidative stress affecting this ratio (Arimon et al., 2015). Understanding the reason for the reading frame preservation rule most likely holds the key to understanding how mutations in the PSEN genes cause fAD.

    (Note: Numbering of PSEN2 exons has changed so while PS2V was originally named after the exclusion of what was then regarded as exon 5, this exon is now numbered as exon 6.)


    . Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease. J Alzheimers Dis. 2016 Apr 4;52(3):781-99. PubMed.

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    . Gamma-secretase gene mutations in familial acne inversa. Science. 2010 Nov 19;330(6007):1065. PubMed.

    . Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010 Apr;133(Pt 4):1143-54. PubMed.

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    . Increased production of beta-amyloid and vulnerability to endoplasmic reticulum stress by an aberrant spliced form of presenilin 2. J Biol Chem. 2001 Jan 19;276(3):2108-14. PubMed.

    . Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of γ-secretase activity. Hum Mol Genet. 2015 Jul 1;24(13):3662-78. Epub 2015 Mar 26 PubMed.

    . Aβ42/Aβ40 Ratios of Presenilin 1 Mutations Correlate with Clinical Onset of Alzheimer's Disease. J Alzheimers Dis. 2018;66(3):939-945. PubMed.

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    . Oxidative stress and lipid peroxidation are upstream of amyloid pathology. Neurobiol Dis. 2015 Dec;84:109-19. Epub 2015 Jun 21 PubMed.

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  1. PSEN2 K115Efs*