Differential, dominant activation and inhibition of notch signalling and APP cleavage by truncations of PSEN1 in human disease deficits
MetadataShow full item record
PRESENILIN1 (PSEN1) is the major locus for mutations causing familial Alzheimer's disease (FAD) and is also mutated 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 the Amyloidβ (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 frame after 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 Appa cleavage 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.
Showing items related by title, author, creator and subject.
Alzheimer's disease-related peptide PS2V plays ancient, conserved roles in suppression of the unfolded protein response under hypoxia and stimulation of ?-secretase activityNik, S.; Newman, M.; Wilson, L.; Ebrahimie, E.; Wells, S.; Musgrave, I.; Verdile, Giuseppe; Martins, R.; Lardelli, M. (2015)The PRESENILIN1 and PRESENILIN2 genes encode structurally related proteases essential for ?-secretase activity. Of nearly 200 PRESENILIN mutations causing early onset, familial Alzheimer's disease (FAD) only the K115Efx10 ...
Qin, S.; Tan, W.; Chen, Younan; Lu, Y.; Lu, X.; Li, Y.; Li, H.; Wang, L.; Cheng, J. (2008)Objective: Hemorrhagic diseases have been considered to be one of the main causes of xenotransplantation failure. To explore the role of the rhesus monkey (Macaca mulatta) coagulation system in a pig-to-human xenotransplantation ...
Valencia, M.; Caparrós-Martín, Jose; Sirerol-Piquer, M.; García-Verdugo, J.; Martínez-Glez, V.; Lapunzina, P.; Temtamy, S.; Aglan, M.; Lund, A.; Nikkels, P.; Ruiz-Perez, V.; Ostergaard, E. (2014)Osteogenesis imperfecta is a genetic condition characterized by bone fragility and recurrent fractures, which in the large majority of patients are caused by defects in the production of type I collagen. Mutations in the ...