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Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.^[3]

Function

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 they either directly regulate gamma-secretase activity or themselves are protease enzymes. Two alternative transcripts of PSEN2 have been identified.^[4]

In melanocytic cells PSEN2 gene expression may be regulated by MITF.^[5]

Interactions

PSEN2 has been shown to interact with:

BCL2-like 1,^[6]
CAPN1,^[7]
CIB1,^[8]
Calsenilin,^[9]^[10]
FHL2,^[11]
FLNB,^[12]
KCNIP4,^[13]
Nicastrin,^[14]^[15] and
UBQLN1.^[16]

References

^ "Human PubMed Reference:".
^ "Mouse PubMed Reference:".
^ Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K (September 1995). "Candidate gene for the chromosome 1 familial Alzheimer's disease locus". Science. 269 (5226): 973–977. doi:10.1126/science.7638622. PMID 7638622.
^ "Entrez Gene: PSEN2 presenilin 2 (Alzheimer disease 4)".
^ Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
^ Passer BJ, Pellegrini L, Vito P, Ganjei JK, D'Adamio L (August 1999). "Interaction of Alzheimer's presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death". J. Biol. Chem. 274 (34): 24007–13. doi:10.1074/jbc.274.34.24007. PMID 10446169.
^ Shinozaki K, Maruyama K, Kume H, Tomita T, Saido TC, Iwatsubo T, Obata K (May 1998). "The presenilin 2 loop domain interacts with the mu-calpain C-terminal region". Int. J. Mol. Med. 1 (5): 797–9. doi:10.3892/ijmm.1.5.797. PMID 9852298.
^ Stabler SM, Ostrowski LL, Janicki SM, Monteiro MJ (June 1999). "A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein". J. Cell Biol. 145 (6): 1277–92. doi:10.1083/jcb.145.6.1277. PMC 2133148. PMID 10366599.
^ Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W (October 1998). "Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment". Nat. Med. 4 (10): 1177–81. doi:10.1038/2673. PMID 9771752.
^ Choi EK, Zaidi NF, Miller JS, Crowley AC, Merriam DE, Lilliehook C, Buxbaum JD, Wasco W (June 2001). "Calsenilin is a substrate for caspase-3 that preferentially interacts with the familial Alzheimer's disease-associated C-terminal fragment of presenilin 2". J. Biol. Chem. 276 (22): 19197–204. doi:10.1074/jbc.M008597200. PMID 11278424.
^ Tanahashi H, Tabira T (September 2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Hum. Mol. Genet. 9 (15): 2281–9. doi:10.1093/oxfordjournals.hmg.a018919. PMID 11001931.
^ Zhang W, Han SW, McKeel DW, Goate A, Wu JY (February 1998). "Interaction of presenilins with the filamin family of actin-binding proteins". J. Neurosci. 18 (3): 914–22. PMC 2042137. PMID 9437013.
^ Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T, Iwatsubo T (April 2002). "Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4". J. Biol. Chem. 277 (17): 14965–75. doi:10.1074/jbc.M200897200. PMID 11847232.
^ Lee SF, Shah S, Li H, Yu C, Han W, Yu G (November 2002). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. 277 (47): 45013–9. doi:10.1074/jbc.M208164200. PMID 12297508.
^ Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (September 2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature. 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067.
^ Mah AL, Perry G, Smith MA, Monteiro MJ (November 2000). "Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation". J. Cell Biol. 151 (4): 847–62. doi:10.1083/jcb.151.4.847. PMC 2169435. PMID 11076969.

External links

GeneReviews/NCBI/NIH/UW entry on Early-Onset Familial Alzheimer Disease

This article on a gene on human chromosome 1 is a stub. You can help Wikipedia by expanding it.

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. アルツハイマー病の遺伝学 genetics of alzheimer disease
2. 認知機能低下および認知症の危険因子 risk factors for cognitive decline and dementia
3. アミロイド疾患の遺伝的要因 genetic factors in the amyloid diseases

English Journal

Thapsigargin affects presenilin-2 but not presenilin-1 regulation in SK-N-BE cells.

Rivabene R1, Visentin S, Piscopo P, Nuccio CD, Crestini A, Svetoni F, Rosa P, Confaloni A.Author information 1Department of Cell Biology and Neuroscience, Istituto Superiore di Sanità, Viale Regina Elena, 299 00161 Rome, Italy.AbstractPresenilin-1 (PS1) and presenilin-2 (PS2) are transmembrane proteins widely expressed in the central nervous system, which function as the catalytic subunits of γ-secretase, the enzyme that releases amyloid-β protein (Aβ) from ectodomain cleaved amyloid precursor protein (APP) by intramembrane proteolysis. Mutations in PS1, PS2, and Aβ protein precursor are involved in the etiology of familial Alzheimer's disease (FAD), while the cause of the sporadic form of AD (SAD) is still not known. However, since similar neuropathological changes have been observed in both FAD and SAD, a common pathway in the etiology of the disease has been suggested. Given that age-related deranged Ca(2+) regulation has been hypothesized to play a role in SAD pathogenesis via PS gene regulation and γ-secretase activity, we studied the in vitro regulation of PS1 and PS2 in the human neuron-like SK-N-BE cell line treated with the specific endoplasmic reticulum (ER) calcium ATPase inhibitor Thapsigargin (THG), to introduce intracellular Ca(2+) perturbations and mimic the altered Ca(2+) homeostasis observed in AD. Our results showed a consistent and significant down-regulation of PS2, while PS1 appeared to be unmodulated. These events were accompanied by oxidative stress and a number of morphological alterations suggestive of the induction of apoptotic machinery. The administration of the antioxidant N-acetylcysteine (NAC) did not revert the THG-induced effects reported, while treatment with the Ca(2+)-independent ER stressor Brefeldin A did not modulate basal PS1 and PS2 expression. Collectively, these results suggest that Ca(2+) fluctuation rather than ER stress and/or oxidative imbalance seems to play an essential role in PS2 regulation and confirm that, despite their strong homology, PS1 and PS2 could play different roles in AD.
Experimental biology and medicine (Maywood, N.J.).Exp Biol Med (Maywood).2014 Feb 1;239(2):213-24. doi: 10.1177/1535370213514317. Epub 2013 Dec 20.
Presenilin-1 (PS1) and presenilin-2 (PS2) are transmembrane proteins widely expressed in the central nervous system, which function as the catalytic subunits of γ-secretase, the enzyme that releases amyloid-β protein (Aβ) from ectodomain cleaved amyloid precursor protein (APP) by intramembrane pr
PMID 24363250

Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice.

Wang P1, Su C, Li R, Wang H, Ren Y, Sun H, Yang J, Sun J, Shi J, Tian J, Jiang S.Author information 1Key Laboratory of Chinese Internal Medicine, Ministry of Education, Beijing University of Chinese Medicine (BUCM), China; Key Laboratory of Pharmacology of Dongzhimen Hospital (BUCM), State Administration of Traditional Chinese Medicine, Beijing, China.AbstractEvidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti-inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β-amyloid aggregation, β-amyloid production, and β-amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40 , Aβ42 , and aggregation of Aβ-derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ-secretase component presenilin-2; and increased the expression of β-amyloid-degrading enzymes, including insulin-degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β-amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin-2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin-degrading enzyme and neprilysin.
Journal of neuroscience research.J Neurosci Res.2014 Feb;92(2):218-31. doi: 10.1002/jnr.23322. Epub 2013 Nov 23.
Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti-inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The u
PMID 24273069

Role of BRI2 in Dementia.

Del Campo M1, Teunissen CE2.Author information 1Neurochemistry Laboratory Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands Alzheimer Center, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.2Neurochemistry Laboratory Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.AbstractAlzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 is a potential regulator of AβPP processing, and it can inhibit the production and fibrillation of Aβ. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology.
Journal of Alzheimer's disease : JAD.J Alzheimers Dis.2014 Jan 28. [Epub ahead of print]
Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-β protein precursor (AβPP), preseni
PMID 24473189

Japanese Journal

統合失調症における選択的スプライシング制御の異常 (第5土曜特集 RNA医学・医療--あらたな診断・治療を拓く) -- (RNA異常による疾患)

眞部孝幸
医学のあゆみ 238(5), 491-497, 2011-07-30
NAID 40018906007

早期発症の認知症とはなにか?

三好功峰
Psychogeriatrics : the official journal of the Japanese Psychogeriatric Society 9(2), 67-72, 2009-06-01
NAID 10025638829

RNA interference silencing of DRAL affects processing of amyloid precursor protein

Tanahashi Hiroshi,Yoshioka Kazuaki
Neuroscience Letters 439(3), 293-297, 2008-07-18
… In a previous study, we reported that Alzheimer's disease-associated presenilin-2 interacts with a LIM-domain protein, namely, DRAL/FHL2/SLIM3. …
NAID 120001135723

Related Pictures

★リンクテーブル★

リンク元	「プレセニリン2」「プレセニリン-2」

「プレセニリン2」

PSEN2
Identifiers
Aliases	PSEN2, AD3L, AD4, CMD1V, PS2, STM2, presenilin 2
External IDs	MGI: 109284 HomoloGene: 386 GeneCards: 5664
Gene ontology
Molecular function	• aspartic-type endopeptidase activity; • endopeptidase activity; • peptidase activity; • protein binding; • hydrolase activity;
Cellular component	• integral component of membrane; • centrosome; • Golgi apparatus; • endoplasmic reticulum membrane; • membrane; • Golgi membrane; • plasma membrane; • integral component of plasma membrane; • protein complex; • neuronal cell body; • nuclear inner membrane; • cell cortex; • Z disc; • apical plasma membrane; • endoplasmic reticulum; • perinuclear region of cytoplasm; • kinetochore; • intracellular;
Biological process	• Notch signaling pathway; • intracellular signal transduction; • response to hypoxia; • ephrin receptor signaling pathway; • protein processing; • positive regulation of catalytic activity; • negative regulation of apoptotic process; • beta-amyloid metabolic process; • proteolysis; • membrane protein ectodomain proteolysis; • membrane protein intracellular domain proteolysis; • positive regulation of apoptotic process; • Notch receptor processing; • amyloid precursor protein catabolic process; • calcium ion transport;
	Sources:Amigo / QuickGO
RNA expression pattern
	; ; ; ;
	More reference expression data
Orthologs
	5664
	19165
	ENSG00000143801
	ENSMUSG00000010609
	P49810
	Q61144
	NM_000447; NM_012486
	NM_001128605; NM_011183
	NP_000438.2; NP_036618.2
	NP_001122077.1; NP_035313.2
	Wikidata
View/Edit Human	View/Edit Mouse

　　[★]

英: presenilin-2
関: プレセニリン-2

「プレセニリン-2」

　　[★]

英: presenilin-2
関: プレセニリン2

[1] "Human PubMed Reference:".

[2] "Mouse PubMed Reference:".

[pmid7638622-3] Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K (September 1995). "Candidate gene for the chromosome 1 familial Alzheimer's disease locus". Science. 269 (5226): 973–977. doi:10.1126/science.7638622. PMID 7638622.

[4] "Entrez Gene: PSEN2 presenilin 2 (Alzheimer disease 4)".

[pmid19067971-5] Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–676. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.

[pmid10446169-6] Passer BJ, Pellegrini L, Vito P, Ganjei JK, D'Adamio L (August 1999). "Interaction of Alzheimer's presenilin-1 and presenilin-2 with Bcl-X(L). A potential role in modulating the threshold of cell death". J. Biol. Chem. 274 (34): 24007–13. doi:10.1074/jbc.274.34.24007. PMID 10446169.

[pmid9852298-7] Shinozaki K, Maruyama K, Kume H, Tomita T, Saido TC, Iwatsubo T, Obata K (May 1998). "The presenilin 2 loop domain interacts with the mu-calpain C-terminal region". Int. J. Mol. Med. 1 (5): 797–9. doi:10.3892/ijmm.1.5.797. PMID 9852298.

[pmid10366599-8] Stabler SM, Ostrowski LL, Janicki SM, Monteiro MJ (June 1999). "A myristoylated calcium-binding protein that preferentially interacts with the Alzheimer's disease presenilin 2 protein". J. Cell Biol. 145 (6): 1277–92. doi:10.1083/jcb.145.6.1277. PMC 2133148. PMID 10366599.

[pmid9771752-9] Buxbaum JD, Choi EK, Luo Y, Lilliehook C, Crowley AC, Merriam DE, Wasco W (October 1998). "Calsenilin: a calcium-binding protein that interacts with the presenilins and regulates the levels of a presenilin fragment". Nat. Med. 4 (10): 1177–81. doi:10.1038/2673. PMID 9771752.

[pmid11278424-10] Choi EK, Zaidi NF, Miller JS, Crowley AC, Merriam DE, Lilliehook C, Buxbaum JD, Wasco W (June 2001). "Calsenilin is a substrate for caspase-3 that preferentially interacts with the familial Alzheimer's disease-associated C-terminal fragment of presenilin 2". J. Biol. Chem. 276 (22): 19197–204. doi:10.1074/jbc.M008597200. PMID 11278424.

[pmid11001931-11] Tanahashi H, Tabira T (September 2000). "Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein". Hum. Mol. Genet. 9 (15): 2281–9. doi:10.1093/oxfordjournals.hmg.a018919. PMID 11001931.

[pmid9437013-12] Zhang W, Han SW, McKeel DW, Goate A, Wu JY (February 1998). "Interaction of presenilins with the filamin family of actin-binding proteins". J. Neurosci. 18 (3): 914–22. PMC 2042137. PMID 9437013.

[pmid11847232-13] Morohashi Y, Hatano N, Ohya S, Takikawa R, Watabiki T, Takasugi N, Imaizumi Y, Tomita T, Iwatsubo T (April 2002). "Molecular cloning and characterization of CALP/KChIP4, a novel EF-hand protein interacting with presenilin 2 and voltage-gated potassium channel subunit Kv4". J. Biol. Chem. 277 (17): 14965–75. doi:10.1074/jbc.M200897200. PMID 11847232.

[pmid12297508-14] Lee SF, Shah S, Li H, Yu C, Han W, Yu G (November 2002). "Mammalian APH-1 interacts with presenilin and nicastrin and is required for intramembrane proteolysis of amyloid-beta precursor protein and Notch". J. Biol. Chem. 277 (47): 45013–9. doi:10.1074/jbc.M208164200. PMID 12297508.

[pmid10993067-15] Yu G, Nishimura M, Arawaka S, Levitan D, Zhang L, Tandon A, Song YQ, Rogaeva E, Chen F, Kawarai T, Supala A, Levesque L, Yu H, Yang DS, Holmes E, Milman P, Liang Y, Zhang DM, Xu DH, Sato C, Rogaev E, Smith M, Janus C, Zhang Y, Aebersold R, Farrer LS, Sorbi S, Bruni A, Fraser P, St George-Hyslop P (September 2000). "Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing". Nature. 407 (6800): 48–54. doi:10.1038/35024009. PMID 10993067.

[pmid11076969-16] Mah AL, Perry G, Smith MA, Monteiro MJ (November 2000). "Identification of ubiquilin, a novel presenilin interactor that increases presenilin protein accumulation". J. Cell Biol. 151 (4): 847–62. doi:10.1083/jcb.151.4.847. PMC 2169435. PMID 11076969.

v t e Protein: cell membrane proteins (other than Cell surface receptor, enzymes, and cytoskeleton)

Arrestin	SAG ARRB1 ARRB2 ARR3

Membrane-spanning 4A	MS4A1 MS4A2 MS4A3 MS4A4A MS4A4E MS4A5 MS4A6A MS4A6E MS4A7 MS4A8B MS4A9 MS4A10 MS4A12 MS4A13 MS4A14 MS4A15 MS4A18

Myelin	Myelin basic protein PMP2 Myelin proteolipid protein PLP1 Myelin oligodendrocyte glycoprotein Myelin-associated glycoprotein Myelin protein zero

Pulmonary surfactant	Pulmonary surfactant-associated protein B Pulmonary surfactant-associated protein C

Tetraspanin	TSPAN1 TSPAN2 TSPAN3 TSPAN4 TSPAN5 TSPAN6 TSPAN7 TSPAN8 TSPAN9 TSPAN10 TSPAN11 TSPAN12 TSPAN13 TSPAN14 TSPAN15 TSPAN16 TSPAN17 TSPAN18 TSPAN19 TSPAN20 TSPAN21 TSPAN22 TSPAN23 TSPAN24 TSPAN25 TSPAN26 TSPAN27 TSPAN28 TSPAN29 TSPAN30 TSPAN31 TSPAN32 TSPAN33 TSPAN34

Other/ungrouped	Calnexin LDL-receptor-related protein-associated protein Neurofibromin 2 Presenilin PSEN1 PSEN2 HFE Phospholipid transfer proteins Dysferlin STRC OTOF

see also other cell membrane protein disorders

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案内

presenilin-2