Literature: A-K ; L-Z ; subject area
Compiled by: Julian Thorpe
Presenilins
|
Please Note: Due to time constraints, the text part of this page has not been updated for some time. However, references are added reasonably frequently. |
Presenilins (presenilin-1 and presenilin-2) are associated with chromosomes 14 and 1, respectively, and it is the mutation of these genes (mainly on chromosome 14) which can lead to a familial form of early-onset AD which accounts for about 5% of all AD cases (e.g. see Chapman et al., 2001 ).
 | Presenilin-1 (PS1) and presenilin-2 (PS2) are 467 and 448 amino acids long, respectively. |
| Both are membrane proteins with multiple transmembrane regions and show a high degree of conservation between species. |
| Presenilins are believed to be sited within the endoplasmic reticulum (Doan et al., 1996) and Golgi . However, PS1 has recently been found to be associated with early endosomes (by subcellular fractionation and immunofluorescence microscopy of PC12 cells; Lah and Levey, 2000). |
| A homologous protein in C. elegans (known as sel-12) has recently been found. This protein has a known involvement in surface receptor signalling via one or more members of the notch family. |
| May form ion channels (have some homology with calcium channels). |
| Checler et al. (2000)
review the role of the
proteasome in modulating the intracellular concentrations of
the presenilins. They consider targeting the proteasome as a possible
point of therapeutic intervention in AD.
|
Presenilins and APP Proteolysis /Notch Signalling
N.B. Also please visit the website of the 'Institut National de la Sante et de la Recherche Medical' for detail further detail on presenilins and APP proteolysis
| Research has associated FAD(familial AD)-linked PS1 variants with elevated A beta 1-42(43)/A beta 1-40 ratios (e.g. Borchelt et al., 1996 ; Lewis et al., 2000 ; S ato et al., 2001 ). |
| Recent studies suggest that presenilins might actually be the gamma-secretases (one of the proteases involved in beta-amyloid production via APP proteolysis ). This has yet to be proven definitively, however. See, e.g., Liet al ., 2000, Wolfe et al ., 1999a and 1999b. Xia, 2000 ). |
| The bulk of reseach results appears to point to the fact that the presenilins are, at the least, intimately involved in APP proteolysis (e.g. as an activator of, or a substrate adaptor for, l -secretase, or via delivery of l -secretase to APP-containing compartments; as suggested by Chen et al., 2000; and see review by Steiner and Haas, 2000 ). |
| However, more recent results from presenilin-deficient embryonic mouse fibroblasts have clouded the issue somewhat (Armogida et al., 2001). Their paper in Nature Cell Biology reported that mouse fibroblasts deficient in PS1, PS2, or both, still produced endogenous secreted and intracellular 40- and 42-amino-acid A beta peptides. However, presenilin deficiency did abolish the release of the Notch intracellular domain (NICD) from Notch. Their data thus showed, that in murine fibroblasts at least, NICD production is presenilin-dependent and that there is a gamma-secretase activity distinct from presenilin. |
| Notch receptor/ligand signalling is a highly-conserved mechanism controlling cell fate decisions throughout the animal kingdom . |
| The presenilins have been implicated in notch signalling via regulation of notch proteolysis ( Levitan and Greenwald, 1998 ; Berezovska et al., 2001 ; Fortini, 2001 ; Martys-Zage et al., 2001 ; Nakajima et al., 2000 ; Selkoe, 2001; and see Hartmann et al., 2001 ). |
| PS1 additionally regulates b-catenin signalling ( Kang et al., 1999) in a GSK-3beta -independent fashion (Palacino et al., 2001 ). As b -catenin also has a secondary role as a transcriptional regulator of the Wnt signal transduction cascade, others ( Anderton et al., 2000 ) have surmised that dysregulation of both the Notch and Wnt pathways might underlie AD progression. Some confirmation for this latter is given by the work of Jackson et al. (2002) which shows that human wild-type tau interacts with wingless pathway components to produce neurofibrillary pathology in Drosophila. |
| Specifically in regard to this latter and Pin1 , b -catenin is a Pin1 target protein . Ryo et al. (2001) have demonstrated (in breast cancer cells) that Pin1 increases the transcription of several b -catenin target genes (inc. cyclin D1 and c-Myc). Pin1 binds a phospo-Ser/Pro motif adjoining the APC(adenomatous polyposis coli protein)-binding site in b -catenin, and thereby inhibits its interaction with APC and increases its relocation to the nucleus. |
| All this latter would suggest that
Pin1 would have a role in any effects upon Notch and Wnt signal
transduction in AD, in addition to its more direct
putative role in mediating APP proteolysis. Back to Top
|
| May be involved in apoptosis regulation: presenilins have been shown to modify the apoptotic response in primary neuronal cultures (see Czech et al., 2000 ). |
| Araki et al. (2000)
have shown - in cultured
neurons - that PS2 overexpression enhances apoptosis and
is associated with a down-regulation of
Bcl-2
(Araki et al., 2001).
|
| Bornemann and Staufenbiel (2000) have generated transgenic mouse lines expressing the human amyloid precursor protein (APP) which displayed many features of AD pathology. Crossbreeding with transgenic mice carrying AD-linked presenilin mutations enhanced the observed pathology. |
| Leutner et al. (2000) used transgenic mice with human PS1 mutations to show evidence of a reduction in the activity of two antioxidant enzymes (Cu/Zn superoxide dismutase and glutathione reductase). |
| Barrow et al. (2000) and Schneider et al. (2001) have demonstrated a disruption of intracellular calcium control and electrophysiological dysfunction in PS1 mutant mice. |
| Armogida et al. (2001) have used presenilin-deficient embryonic mouse fibroblasts to show that the production of endogenous secreted and intracellular 40- and 42-amino-acid A beta peptides is unaffected. However, presenilin deficiency did abolish the release of the Notch intracellular domain (NICD) from Notch. Their data thus showed, that in murine fibroblasts at least, NICD production is presenilin-dependent and that there is a gamma-secretase activity distinct from presenilin. |
| Mudher and Lovestone (2002) suggest that animal models have taken us tantalisingly close to the answer to plaque/tangle inter-relationships. These authors report that as (in human brain) "mutations in tau..." (that lead to the FTD disorders) "...give rise to tau-inclusion tangles but not plaques and yet mutations in APP or.... presenilin ...give rise to both plaques and tangles almost proves that amyloid pathology occurs upstream of tau pathology " (my italics). |
(These journals include: Neurology, Neurobiology of Disease, Journal of Neurochemistry, Alzheimer's Disease Review)
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