PS1 and PS2 are important determinants of gamma-secretase activity responsible for the proteolytic cleavage of the amyloid precursor protein (APP; 104760) and the NOTCH receptor protein (600725). Kopan and Goate (2000) reviewed evidence that presenilins are founding members of a novel class of aspartyl proteases that hydrolyze peptide bonds embedded within a membrane. The authors stated that although PS1 and PS2 both appear to be gamma secretases, it is not clear if the 2 enzymes normally have similar or different substrates, since they reside in different complexes. They proposed that the key to the regulation of cleavage may depend on the characterization of other proteins that are present in the high molecular weight complex that contains gamma-secretase activity.
Psn encodes a product involved in cell fate commitment which is a component of the cytoplasm ; it is expressed in the embryo (central nervous system ), larva (eye-antennal disc and leg disc ) and ovary (follicle cell , nurse cell , nurse cell and oocyte ).
NCBI Summary:
Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Two alternative transcripts of PSEN2 have been identified.
General function
Cytoskeleton, Cell death/survival, Anti-apoptotic
Comment
cytoskeleton organization and biogenesis
Notch receptor processing: Psn is required for activity and nuclear access of Notch Struhl and Greenwald (1999)
Psn and nct (nicastrin) have a novel function, independent of their role in Notch signaling, that relates to the organization of the spectrin cytoskeleton. Lopez-Schier and Johnston, (2002)
Cellular localization
Cytoplasmic, Cytoskeleton
Comment
Ovarian function
Oogenesis, ring canal formation
Comment
Differential expression of presenilin-alpha and -beta (PSalpha and PSbeta) in Xenopus laevis: embryonic phosphorylation of PSalpha
Watanabe Y, et al .
Mutations in genes encoding the highly homologous proteins, presenilin-1 and -2 (PS1 and PS2), are linked to the development of early-onset Alzheimer's disease. On the other hand, presenilins are known to play a critical role(s) in cell fate decisions during embryonic development in Caenorhabditis elegans. The messenger RNAs (mRNAs) of amphibian presenilin homologues PSalpha and PSbeta are most abundantly synthesized in the brain and the ovary, but are differentially degraded upon oocyte maturation and at the midblastula transition (MBT), respectively. In this study, we examined the spatiotemporal distribution of PSalpha and PSbeta proteins and their post-translational modification. The results were essentially consistent with the mRNA data and revealed moreover that PSalpha was present exclusively as processed molecules in the early embryos, while PSbeta was present mainly as unprocessed molecules (90%). Furthermore, the C-terminal fragment (CTF) of PSalpha was phosphorylated upon oocyte maturation and dephosphorylated at MBT, while no phosphorylation of the PSbeta CTF was detectable. Human PS1 CTF exogenously injected was also phosphorylated in Xenopus oocytes induced to mature in vitro by progesterone treatment. Two phosphorylation loci were mapped at Thr(320) and Ser(334) in the hydrophilic loop region of PSalpha. Our results suggest that PS1 and PS2 may play different roles under physiological conditions despite their high structural similarity.
Rimon E, et al reported
Gonadotropin-induced gene regulation in human granulosa cells obtained from IVF patients and Modulation of genes coding for growth factors and their receptors and genes involved in cancer and other diseases.
Gonadotropins play a crucial role in ovarian homeostasis and fertilization. However, hypergonadotropin stimulation has been thought to increase the risk for ovarian cancer. Moreover, some correlation between high levels of gonadotropins in the circulation and Alzheimer's disease has been implicated, with no clear evidence on the molecular mechanism involved. Using DNA microarray technology and RNA from gonadotropin-stimulated human granulosa cells, which comprise the main bulk of the ovarian follicular somatic cells, we discovered that stimulation of cells with saturating doses of gonadotropins gives rise to the expression of genes coding for presenilin 1 and 2, along with the up-regulation of genes involved in steroidogenesis such as StAR, cytochrome P450scc enzyme system and aromatase. Moreover, gonadotropin stimulation in these cells dramatically elevates activity of genes coding for epiregulin and amphiregulin, which can bind and activate the EGF receptor and ERB4. These gene products may elevate the risk for ovarian, breast, endometrial and other non-gynecological cancers. Gene transcripts for oncogenes and tumor markers such as pleiomorphic adenoma gene-like 1 (Plagl1) tumor antigen (L6) and claudin 3 were markedly elevated following LH and FSH stimulation. In parallel, downregulation in ovarian cancer 1 (DOC1) and suppression of tumorigenicity (ST5) genes was observed, suggesting a potential increase for cancer development. In contrast, increase in tumor rejection antigen (gp96) 1 and decrease in connective tissue growth factor (CTGF), transforming growth factor-beta 1 induced transcript 1 (TGFB1Il), pim-1 oncogene (PIM1), v-maf musculoaponeurotic fibrosarcoma oncogene homologue (MAF) and CD24 antigen may be associated with a decreased risk for specific cancers. In conclusion, gonadotropin stimulation may modulate specific sets of gene transcripts that may either elevate or reduce the risk for specific diseases.
Follicle stages
Antral, Preovulatory, oogenesis, cyst
Comment
Phenotypes
Mutations
1 mutations
Species: D. melanogaster
Mutation name: None
type: null mutation fertility: embryonic lethal Comment: Delta signaling from the germ line controls the proliferation and differentiation of the somatic follicle cells during Drosophila oogenesis. L?-Schier H et al. The body axes of Drosophila are established during oogenesis through reciprocal interactions between the germ line cells and the somatic follicle cells that surround them. The Notch pathway is required at two stages in this process: first, for the migration of the follicle cells around the germ line cyst and, later, for the polarization of the anterior-posterior (A-P) axis of the oocyte. Its function in these events, however, has remained controversial. Using clonal analysis, we show that Notch signaling controls cell proliferation and differentiation in the whole follicular epithelium. Notch mutant follicle cells remain in a precursor state and fail to switch from the mitotic cell cycle to the endocycle. Furthermore, removal of Delta from the germ line produces an identical phenotype, showing that Delta signals from the germ cells to control the timing of follicle cell differentiation. This explains the axis formation defects in Notch mutants, which arise because undifferentiated posterior follicle cells cannot signal to polarize the oocyte. Delta also signals from the germ line to Notch in the soma earlier in oogenesis to control the differentiation of the polar and stalk follicle cells. The germ line therefore regulates the development of the follicle cells through two complementary signaling pathways: Gurken signals twice to control spatial patterning, whereas Delta signals twice to exert temporal control.
Psn- embryos (lacking maternal and zygotic Psn product) are identical to those lacking maternal and zygotic Notch (N) product. Clusters of neuroblasts segregate at positions usually occupied by single neuroblasts. Extensive neural hyperplasia occurs, larvae lack dorsal and ventral cuticle. Number of embryonic midline cells is reduced. Clones of Psn- cells induced in imaginal discs cause phenotypes similar to those caused by the N- condition: in the wing scalloping and vein thickening occur, margins are interrupted and veins are miss-spaced. Large homozygous mutant clones that presumably include the polar cell precursors lead to fusions between adjacent egg chambers. Mutant epithelial follicle cells continue to divide after stage 6. When mutant clones include the follicle cells at the posterior of the egg chamber, the germinal vesicle often fails to migrate and remains at the posterior pole Lopez-Schier and St. Johnston (2001) .
In mutant clones in the follicle cells the normal organization of the spectrin cytoskeleton is disrupted Lopez-Schier and Johnston (2002)