Presenilin 1 (PSEN1)

FAD; AD3; PS1; PSNL1; S182; Alzheimer Disease 3; Protein S182; Presenilin-1 CTF12

SPN	U644
HGNC	9508
MGI	1202717
PubMed	22461631
RGD	3425
UniProt	P49768
Wiki	PSEN1

Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (beta-amyloid precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. Stimulates cell-cell adhesion though its association with the E-cadherin/catenin complex. Under conditions of apoptosis or calcium influx, cleaves E-cadherin promoting the disassembly of the E-cadherin/catenin complex and increasing the pool of cytoplasmic beta-catenin, thus negatively regulating Wnt signaling. May also play a role in hematopoiesis.

Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or in 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 they either directly regulate gamma secretase activity or themselves are protease enzymes. Multiple alternatively spliced transcript variants have been identified for this gene, the full-length natures of only some have been determined.

Reference

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"Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue."
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"Proteolytic processing of the Alzheimer disease-associated presenilin-1 generates an in vivo substrate for protein kinase C."
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"Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa C-terminal fragment are death substrates for proteases of the caspase family."
Biochemistry 37:2263-2270(1998) [PubMed] [Europe PMC] [Abstract]

"Direct association of presenilin-1 with beta-catenin."
FEBS Lett. 433:73-77(1998) [PubMed] [Europe PMC] [Abstract]

"Interaction of presenilins with the filamin family of actin-binding proteins."
J. Neurosci. 18:914-922(1998) [PubMed] [Europe PMC] [Abstract]

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Biochemistry 38:14600-14605(1999) [PubMed] [Europe PMC] [Abstract]

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J. Biol. Chem. 274:32543-32546(1999) [PubMed] [Europe PMC] [Abstract]

"Cell surface presenilin-1 participates in the gamma-secretase-like proteolysis of Notch."
J. Biol. Chem. 274:36801-36807(1999) [PubMed] [Europe PMC] [Abstract]

"Presenilins interact with armadillo proteins including neural-specific plakophilin-related protein and beta-catenin."
J. Neurochem. 72:999-1008(1999) [PubMed] [Europe PMC] [Abstract]

"Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and gamma-secretase activity."
Nature 398:513-517(1999) [PubMed] [Europe PMC] [Abstract]

"Aspartate mutations in presenilin and gamma-secretase inhibitors both impair notch1 proteolysis and nuclear translocation with relative preservation of notch1 signaling."
J. Neurochem. 75:583-593(2000) [PubMed] [Europe PMC] [Abstract]

"Separation of presenilin function in amyloid beta-peptide generation and endoproteolysis of Notch."
Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000) [PubMed] [Europe PMC] [Abstract]

"Presenilin-1 binds cytoplasmic epithelial cadherin, inhibits cadherin/p120 association, and regulates stability and function of the cadherin/catenin adhesion complex."
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"Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane."
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"Reconstitution of gamma-secretase activity."
Nat. Cell Biol. 5:486-488(2003) [PubMed] [Europe PMC] [Abstract]

"Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2."
Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003) [PubMed] [Europe PMC] [Abstract]

"An unappreciated role for RNA surveillance."
Genome Biol. 5:R8.1-R8.16(2004) [PubMed] [Europe PMC] [Abstract]

"Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis."
J. Biol. Chem. 279:1585-1593(2004) [PubMed] [Europe PMC] [Abstract]

"Consensus analysis of signal peptide peptidase and homologous human aspartic proteases reveals opposite topology of catalytic domains compared with presenilins."
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"Conserved residues within the putative active site of gamma-secretase differentially influence enzyme activity and inhibitor binding."
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"Cadherins mediate both the association between PS1 and beta-catenin and the effects of PS1 on beta-catenin stability."
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"Global, in vivo, and site-specific phosphorylation dynamics in signaling networks."
Cell 127:635-648(2006) [PubMed] [Europe PMC] [Abstract]

"C-terminal PAL motif of presenilin and presenilin homologues required for normal active site conformation."
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"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle."
Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract]

"A quantitative atlas of mitotic phosphorylation."
Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract]

"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions."
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"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis."
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"Gamma-secretase gene mutations in familial acne inversa."
Science 330:1065-1065(2010) [PubMed] [Europe PMC] [Abstract]

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"The structure of the presenilin 1 (S182) gene and identification of six novel mutations in early onset AD families."
Nat. Genet. 11:219-222(1995) [PubMed] [Europe PMC] [Abstract]

"Three different mutations of presenilin 1 gene in early-onset Alzheimer's disease families."
Neurosci. Lett. 208:195-198(1996) [PubMed] [Europe PMC] [Abstract]

"Early-onset Alzheimer's disease with a presenilin-1 mutation at the site corresponding to the Volga German presenilin-2 mutation."
Ann. Neurol. 42:124-128(1997) [PubMed] [Europe PMC] [Abstract]

"E280A PS-1 mutation causes Alzheimer's disease but age of onset is not modified by ApoE alleles."
Hum. Mutat. 10:186-195(1997) [PubMed] [Europe PMC] [Abstract]

"Two novel (M233T and R278T) presenilin-1 mutations in early-onset Alzheimer's disease pedigrees and preliminary evidence for association of presenilin-1 mutations with a novel phenotype."
NeuroReport 8:1537-1542(1997) [PubMed] [Europe PMC] [Abstract]

"A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with early onset Alzheimer disease."
Ann. Genet. 41:149-153(1998) [PubMed] [Europe PMC] [Abstract]

"The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause Alzheimer's disease."
Ann. Neurol. 44:965-967(1998) [PubMed] [Europe PMC] [Abstract]

"Missense mutation E318G of the presenilin-1 gene appears to be a nonpathogenic polymorphism."
Ann. Neurol. 44:985-986(1998) [PubMed] [Europe PMC] [Abstract]

"Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease."
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"Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene."
Hum. Mutat. 11:216-221(1998) [PubMed] [Europe PMC] [Abstract]

"Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a French family with early-onset Alzheimer's disease and transmission study by mismatch enhanced allele specific amplification."
Hum. Mutat. 11:481-481(1998) [PubMed] [Europe PMC] [Abstract]

"De novo presenilin 1 mutations are rare in clinically sporadic, early onset Alzheimer's disease cases."
J. Med. Genet. 35:672-673(1998) [PubMed] [Europe PMC] [Abstract]

"A novel Polish presenilin-1 mutation (P117L) is associated with familial Alzheimer's disease and leads to death as early as the age of 28 years."
NeuroReport 9:217-221(1998) [PubMed] [Europe PMC] [Abstract]

"Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease."
NeuroReport 9:3335-3339(1998) [PubMed] [Europe PMC] [Abstract]

"The Glu318Gly substitution in presenilin 1 is not causally related to Alzheimer disease."
Am. J. Hum. Genet. 64:290-292(1999) [PubMed] [Europe PMC] [Abstract]

"Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum."
Am. J. Hum. Genet. 65:664-670(1999) [PubMed] [Europe PMC] [Abstract]

"Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset Alzheimer's disease in the UK."
Hum. Mutat. 13:256-256(1999) [PubMed] [Europe PMC] [Abstract]

"A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a Japanese family with presenile familial Alzheimer's disease."
Hum. Mutat. 14:90-90(1999) [PubMed] [Europe PMC] [Abstract]

"DGGE method for the mutational analysis of the coding and proximal promoter regions of the Alzheimer's disease presenilin-1 gene: two novel mutations."
Hum. Mutat. 14:433-439(1999) [PubMed] [Europe PMC] [Abstract]

"A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures."
Neurology 52:566-570(1999) [PubMed] [Europe PMC] [Abstract]

"Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of the presenilin-1 gene."
NeuroReport 10:503-507(1999) [PubMed] [Europe PMC] [Abstract]

"A presenilin-1 Thr116Asn substitution in a family with early-onset Alzheimer's disease."
NeuroReport 10:2255-2260(1999) [PubMed] [Europe PMC] [Abstract]

"High prevalence of pathogenic mutations in patients with early-onset dementia detected by sequence analyses of four different genes."
Am. J. Hum. Genet. 66:110-117(2000) [PubMed] [Europe PMC] [Abstract]

"Novel presenilin-1 mutation with widespread cortical amyloid deposition but limited cerebral amyloid angiopathy."
J. Neurol. Neurosurg. Psych. 68:220-223(2000) [PubMed] [Europe PMC] [Abstract]

"The presenilin 1 C92S mutation increases abeta 42 production."
Biochem. Biophys. Res. Commun. 277:261-263(2000) [PubMed] [Europe PMC] [Abstract]

"Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation."
Neurology 55:1577-1578(2000) [PubMed] [Europe PMC] [Abstract]

Erratum
Hum. Genet. 109:242-242(2001)

"A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families."
JAMA 286:2257-2263(2001) [PubMed] [Europe PMC] [Abstract]

"Molecular evidence of presenilin 1 mutation in familial early onset dementia."
Am. J. Med. Genet. 114:292-298(2002) [PubMed] [Europe PMC] [Abstract]

"Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Abeta 42 production."
Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002) [PubMed] [Europe PMC] [Abstract]

"A novel presenilin 1 mutation (L174 M) in a large Cuban family with early onset Alzheimer disease."
Neurogenetics 4:97-104(2002) [PubMed] [Europe PMC] [Abstract]

"Presenilin-1 mutation L271V results in altered exon 8 splicing and Alzheimer's disease with non-cored plaques and no neuritic dystrophy."
J. Biol. Chem. 278:6748-6754(2003) [PubMed] [Europe PMC] [Abstract]

"Mutations of presenilin genes in dilated cardiomyopathy and heart failure."
Am. J. Hum. Genet. 79:1030-1039(2006) [PubMed] [Europe PMC] [Abstract]

"Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin syndrome."
Am. J. Hum. Genet. 82:1334-1341(2008) [PubMed] [Europe PMC] [Abstract]

"Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma."
Nature 469:539-542(2011) [PubMed] [Europe PMC] [Abstract]

"Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish dementia patients."
Neurobiol. Aging 33:1850.E17-1850.E27(2012) [PubMed] [Europe PMC] [Abstract]