Differential, dominant activation and inhibition of notch signalling and APP cleavage by truncations of PSEN1 in human disease deficits

M.R. Newman, L.D. Wilson, Giuseppe Verdile, A. Lim, I. Khan, S.H. Moussavi Nik, S.E. Pursglove, G. Chapman, Ralph Martins, M.T. Lardelli

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    43 Citations (Scopus)


    PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is alsomutated in Pick disease of brain, familial acne inversa and dilated cardiomyopathy. It is a critical facilitator of Notch signalling and many other signalling pathways and protein cleavage events including production of theAmyloidb (Aβ) peptide from the AMYLOID BETA A4 PRECURSOR PROTEIN (APP). We previously reported that interference with splicing of transcripts of the zebrafish orthologue of PSEN1 creates dominant negative effects on Notch signalling. Here,we extend this work to show that various truncations of human PSEN1 (or zebrafish Psen1) protein have starkly differential effects on Notch signalling and cleavage of zebrafish Appa (a paralogue of human APP). Different truncations can suppress or stimulate Notch signalling but not Appa cleavage and vice versa. The G183V mutation possibly causing Pick disease causes production of aberrant transcripts truncating the open reading frameafter exon 5 sequence. We show that the truncated protein potentially translated from these transcripts avidly incorporates into very stable Psen1-dependent higher molecular weight complexes and suppresses cleavage of Appa but not Notch signalling. In contrast, the truncated protein potentially produced by the P242LfsX11 acne inversa mutation has no effect on Appac leavage but,unexpectedly, enhances Notch signalling. Our results suggest novel hypotheses for the pathological mechanisms underlying these diseases and illustrate the importance of investigating the function of dominant mutations at physiologically relevant expression levels and in the normally heterozygous state in which they cause human disease rather than in isolation from healthy alleles. © The Author 2013. Published by Oxford University Press. All rights reserved.
    Original languageEnglish
    Pages (from-to)602-617
    Number of pages26
    JournalHuman Molecular Genetics
    Issue number3
    Early online date18 Sept 2013
    Publication statusPublished - Feb 2014


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