presenilin 1

Target not currently curated in GtoImmuPdb

Target id: 2402

Nomenclature: presenilin 1

Gene and Protein Information
Species	TM	AA	Chromosomal Location	Gene Symbol	Gene Name	Reference
Human	9	467	14q24.2	PSEN1	presenilin 1
Mouse	9	467	12 38.84 cM	Psen1	presenilin 1
Rat	9	468	6q24	Psen1	presenilin 1

Previous and Unofficial Names
AD3 \| Ad3h \| FAD \| PS1

Database Links
Specialist databases
MEROPS	A22.001 (Hs)
Other databases
Alphafold	P49768 (Hs), P49769 (Mm), P97887 (Rn)
BRENDA	3.4.23.-
ChEMBL Target	CHEMBL2473 (Hs)
Ensembl Gene	ENSG00000080815 (Hs), ENSMUSG00000019969 (Mm), ENSRNOG00000009110 (Rn)
Entrez Gene	5663 (Hs), 19164 (Mm), 29192 (Rn)
Human Protein Atlas	ENSG00000080815 (Hs)
KEGG Enzyme	3.4.23.-
KEGG Gene	hsa:5663 (Hs), mmu:19164 (Mm), rno:29192 (Rn)
OMIM	104311 (Hs)
Orphanet	ORPHA118099 (Hs)
Pharos	P49768 (Hs)
RefSeq Nucleotide	NM_000021 (Hs), NM_007318 (Hs), NM_008943 (Mm), NM_019163 (Rn)
RefSeq Protein	NP_000012 (Hs), NP_015557 (Hs), NP_032969 (Mm), NP_062036 (Rn)
UniProtKB	P49768 (Hs), P49769 (Mm), P97887 (Rn)
Wikipedia	PSEN1 (Hs)

Enzyme Reaction

EC Number: 3.4.23.-

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Inhibitors

Key to terms and symbols

View all chemical structures

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Ligand		Sp.	Action	Value	Parameter	Reference
begacestat		Hs	Inhibition	7.8	pEC₅₀	6
⤷	pEC₅₀ 7.8 (EC₅₀ 1.48x10^-8 M) [6]
CHF-5074		Hs	Binding	4.4	pEC₅₀	9
⤷	pEC₅₀ 4.4 (EC₅₀ 4x10^-5 M) [9]
avagacestat		Hs	Inhibition	9.5	pIC₅₀	1
⤷	pIC₅₀ 9.5 (IC₅₀ 3x10^-10 M) [1]
ELND006		Hs	Inhibition	9.5	pIC₅₀	7
⤷	pIC₅₀ 9.5 (IC₅₀ 3.4x10^-10 M) [7] Description: A-beta release assay
SCH-900229		Hs	Inhibition	8.9 – 9.0	pIC₅₀	8
⤷	pIC₅₀ 8.9 – 9.0 (IC₅₀ 1.3x10^-9 – 1x10^-9 M) [8] Description: Data range indicates inhibition of Aβ42 or Aβ40 production.
RO4929097		Hs	Inhibition	8.4	pIC₅₀	4
⤷	pIC₅₀ 8.4 (IC₅₀ 4x10^-9 M) [4]
semagacestat		Hs	Inhibition	7.8	pIC₅₀	3
⤷	pIC₅₀ 7.8 (IC₅₀ 1.5x10^-8 M) [3]
AZ4800		Hs	Inhibition	7.6	pIC₅₀	2
⤷	pIC₅₀ 7.6 (IC₅₀ 2.6x10^-8 M) [2]

Immuno Process Associations

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immuno Process:

Immune system development

Immuno Process:

Cytokine production & signalling

Phenotypes, Alleles and Disease Models

Mouse data from MGI

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Allele	Composition & genetic background	Accession	Phenotype Id	Phenotype	Reference
Cx3cr1⁺\|Cx3cr1^tm1Litt\|Psen1^tm1Mpm\|Tg(APPSwe,tauP301L)1Lfa\|Tg(Thy1-YFPH)2Jrs	Cx3cr1^tm1Litt/Cx3cr1⁺,Psen1^tm1Mpm/Psen1^tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0 involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:1202717 MGI:1333815 MGI:2684637 MGI:3497950	MP:0000136	abnormal microglial cell morphology	PMID: 20305648
Cx3cr1⁺\|Cx3cr1^tm1Litt\|Psen1^tm1Mpm\|Tg(APPSwe,tauP301L)1Lfa\|Tg(Thy1-YFPH)2Jrs	Cx3cr1^tm1Litt/Cx3cr1⁺,Psen1^tm1Mpm/Psen1^tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0 involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:1202717 MGI:1333815 MGI:2684637 MGI:3497950	MP:0003691	abnormal microglial cell physiology	PMID: 20305648
Cx3cr1⁺\|Cx3cr1^tm1Litt\|Psen1^tm1Mpm\|Tg(APPSwe,tauP301L)1Lfa\|Tg(Thy1-YFPH)2Jrs	Cx3cr1^tm1Litt/Cx3cr1⁺,Psen1^tm1Mpm/Psen1^tm1Mpm,Tg(APPSwe,tauP301L)1Lfa/0,Tg(Thy1-YFPH)2Jrs/0 involves: 129P2/OlaHsd * 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA	MGI:1202717 MGI:1333815 MGI:2684637 MGI:3497950	MP:0003224	neuron degeneration	PMID: 20305648

Clinically-Relevant Mutations and Pathophysiology

Disease:

Acne inversa, familial, 3; ACNINV3

Synonyms:	Hidradenitis suppurativa [Disease Ontology: DOID:2280]
Disease Ontology:	DOID:2280
OMIM:	613737

Disease:

Alzheimer disease 3

Synonyms:	Alzheimer's disease [Disease Ontology: DOID:10652] Early-onset autosomal dominant Alzheimer disease [Orphanet: ORPHA1020]
Disease Ontology:	DOID:10652
OMIM:	607822
Orphanet:	ORPHA1020

Disease:

Behavioral variant of frontotemporal dementia

Orphanet:

ORPHA275864

Disease:

Cardiomyopathy, dilated, 1U; CMD1U

Synonyms:	Dilated cardiomyopathy [Disease Ontology: DOID:12930] Familial isolated dilated cardiomyopathy [Orphanet: ORPHA154]
Disease Ontology:	DOID:12930
OMIM:	613694
Orphanet:	ORPHA154

Disease:

Frontotemporal dementia

Disease Ontology:	DOID:9255
OMIM:	600274

Disease:

Progressive non-fluent aphasia

Orphanet:

ORPHA100070

References:

Click column headers to sort

Type	Species	Amino acid change	Nucleotide change	Description	Reference
Missense	Human	P264L	g.49976C>T	The nucleotide transition occurs in exon 8	5

Disease:

Semantic dementia

Orphanet:

ORPHA100069

References

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1. Alzheimer Research Forum. DRUGS IN CLINICAL TRIALS: BMS-708163. Accessed on 06/09/2013. Modified on 06/09/2013. Alzheimer Research Forum, http://www.alzforum.org/drg/drc/detail.asp?id=124

2. Borgegard T, Juréus A, Olsson F, Rosqvist S, Sabirsh A, Rotticci D, Paulsen K, Klintenberg R, Yan H, Waldman M et al.. (2012) First and second generation γ-secretase modulators (GSMs) modulate amyloid-β (Aβ) peptide production through different mechanisms. J Biol Chem, 287 (15): 11810-9. [PMID:22334705]

3. Kreft AF, Martone R, Porte A. (2009) Recent advances in the identification of gamma-secretase inhibitors to clinically test the Abeta oligomer hypothesis of Alzheimer's disease. J Med Chem, 52 (20): 6169-88. [PMID:19694467]

4. Luistro L, He W, Smith M, Packman K, Vilenchik M, Carvajal D, Roberts J, Cai J, Berkofsky-Fessler W, Hilton H et al.. (2009) Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. Cancer Res, 69 (19): 7672-80. [PMID:19773430]

5. Mahoney CJ, Downey LE, Beck J, Liang Y, Mead S, Perry RJ, Warren JD. (2013) The presenilin 1 P264L mutation presenting as non-fluent/agrammatic primary progressive aphasia. J Alzheimers Dis, 36 (2): 239-43. [PMID:23579325]

6. Martone RL, Zhou H, Atchison K, Comery T, Xu JZ, Huang X, Gong X, Jin M, Kreft A, Harrison B et al.. (2009) Begacestat (GSI-953): a novel, selective thiophene sulfonamide inhibitor of amyloid precursor protein gamma-secretase for the treatment of Alzheimer's disease. J Pharmacol Exp Ther, 331 (2): 598-608. [PMID:19671883]

7. Probst G, Aubele DL, Bowers S, Dressen D, Garofalo AW, Hom RK, Konradi AW, Marugg JL, Mattson MN, Neitzel ML et al.. (2013) Discovery of (R)-4-cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (ELND006) and (R)-4-cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline (ELND007): metabolically stable γ-secretase Inhibitors that selectively inhibit the production of amyloid-β over Notch. J Med Chem, 56 (13): 5261-74. [PMID:23713656]

8. Wu WL, Domalski M, Burnett DA, Josien H, Bara T, Rajagopalan M, Xu R, Clader J, Greenlee WJ, Brunskill A et al.. (2012) Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer's Disease. ACS Med Chem Lett, 3 (11): 892-6. [PMID:24900404]

9. Xin Z, Peng H, Zhang A, Talreja T, Kumaravel G, Xu L, Rohde E, Jung MY, Shackett MN, Kocisko D et al.. (2011) Discovery of 4-aminomethylphenylacetic acids as γ-secretase modulators via a scaffold design approach. Bioorg Med Chem Lett, 21 (24): 7277-80. [PMID:22061640]