The Presenilin proteins are essential facilitators of numerous developmental and cell signaling pathways. Point mutations in the human PRESENILIN genes (including mutations affecting splicing) have been linked to familial Alzheimer's disease. Zebrafish possess orthologues of the human PRESENILIN1 and PRESENILIN2 genes. We previously investigated forced aberrant splicing of zebrafish presenilin1 and discovered that high levels of incorporation into spliced transcripts of the intron cognate with human PRESENILIN1 intron 8 resulted in little or no change in Presenilin1 protein level and no identifiable embryonic phenotype. We now demonstrate that zebrafish embryos maintain relatively stable levels of normal Presenilin1 transcript and protein despite accumulating large amounts of aberrantly spliced presenilin1 transcript. We also show that increasing the levels of Presenilin1 protein decreases normal presenilin1 transcription. These two independent lines of evidence and the fact that blockage of Presenilin1 translation increases presenilin1 transcription support that regulation of presenilin1 transcript levels plays a major role in the homeostasis of Presenilin1 protein levels, presumably via a feedback mechanism that monitors the levels of Presenilin1 protein. ; Morgan Newman, Svanhild Nornes, Ralph N. Martins, Michael T. Lardelli