View source for Presenilin

{{Infobox protein family
| Symbol = Presenilin
| Name = Presenilin
| image = 2KR6.pdb.png
| width = 
| caption = Solution structure of the human presenilin-1 CTF subunit.<ref name=doetsch>{{Cite journal
 | pmid = 20445084
| pmc = 2906861
| year = 2010
| author1 = Sobhanifar
| first1 = S
| title = Structural investigation of the C-terminal catalytic fragment of presenilin 1
| journal = Proceedings of the National Academy of Sciences
| volume = 107
| issue = 21
| pages = 9644–9
| last2 = Schneider
| first2 = B
| last3 = Löhr
| first3 = F
| last4 = Gottstein
| first4 = D
| last5 = Ikeya
| first5 = T
| last6 = Mlynarczyk
| first6 = K
| last7 = Pulawski
| first7 = W
| last8 = Ghoshdastider
| first8 = U
| last9 = Kolinski
| first9 = M
| last10 = Filipek
| first10 = S
| last11 = Güntert
| first11 = P
| last12 = Bernhard
| first12 = F
| last13 = Dötsch
| first13 = V
| doi = 10.1073/pnas.1000778107
}}</ref><ref name="Doetsch_2010">{{PDB|2KR6}}; {{cite journal | author = Doetsch V | title = Solution structure of presenilin-1 CTF subunit | journal = To be published | year = 2010 | doi= 10.2210/pdb2kr6/pdb}}</ref>
| Pfam = PF01080
| Pfam_clan = CL0130
| InterPro = IPR001108
| SMART = 
| PROSITE = 
| SCOP = 
| MEROPS = A22
| TCDB = 1.A.54
| OPM family = 244
| OPM protein = 4hyg
| PDB = 
}}
{{infobox protein
|Name=[[PSEN1|presenilin 1<br />(Alzheimer's disease 3)]]
|caption=
|image=
|width=
|HGNCid=9508
|Symbol=[[PSEN1]]
|AltSymbols=AD3
|EntrezGene=5663
|OMIM=104311
|RefSeq=NM_000021
|UniProt=P49768
|PDB=
|ECnumber = 3.4.23.-
|Chromosome=14
|Arm=q
|Band=24.3
|LocusSupplementaryData=
}}
{{infobox protein
|Name=[[PSEN2|presenilin 2<br />(Alzheimer's disease 4)]]
|caption=
|image=
|width=
|HGNCid=9509
|Symbol=[[PSEN2]]
|AltSymbols=AD4
|EntrezGene=5664
|OMIM=600759
|RefSeq=NM_000447
|UniProt=P49810
|PDB=
|ECnumber= 3.4.23.-
|Chromosome=1
|Arm=q
|Band=31
|LocusSupplementaryData=-q42
}}

'''Presenilins''' are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the [[gamma-secretase]] [[intramembrane protease]] complex. They were first identified in screens for mutations causing early onset forms of familial [[Alzheimer's Disease]] by [[Peter St George-Hyslop]] at the [[Centre for Research in Neurodegenerative Diseases]] at the [[University of Toronto]], and now also at the [[University of Cambridge]].<ref name="pmid7596406">{{cite journal |vauthors=Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, Chi H, Lin C, Li G, Holman K | title = Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease | journal = Nature | volume = 375 | issue = 6534 | pages = 754–60 |date=June 1995 | pmid = 7596406 | doi = 10.1038/375754a0 | url =  }}</ref> Vertebrates have two presenilin [[gene]]s, called ''[[PSEN1]]'' (located on [[chromosome 14]] in humans) that encodes presenilin 1 (PS-1) and ''[[PSEN2]]'' (on [[chromosome 1]] in humans) that codes for  presenilin 2 (PS-2).<ref name="pmid7638622">{{cite journal |vauthors=Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K, Crowley AC, Fu YH, Guenette SY, Galas D, Nemens E, Wijsman EM, Bird TD, Schellenberg GD, Tanzi RE | title = Candidate gene for the chromosome 1 familial Alzheimer's disease locus | journal = Science | volume = 269 | issue = 5226 | pages = 973–977 | date=September 1995| pmid = 7638622 | pmc =  | doi =10.1126/science.7638622  }}</ref> Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm ''[[Caenorhabditis elegans|C. elegans]]'' has two genes that resemble the presenilins and appear to be functionally similar, [[sel-12]] and [[hop-1]].<ref name="pmid17047361">{{cite journal |vauthors=Smialowska A, Baumeister R | title = Presenilin function in Caenorhabditis elegans | journal = Neurodegener Dis | volume = 3 | issue = 4–5 | pages = 227–32 | year = 2006 | pmid = 17047361 | doi = 10.1159/000095260 | url =  }}</ref>

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a large [[N-terminal]] and a smaller [[C-terminal]] fragment that together form part of the functional protein.<ref name=doetsch /> Cleavage of presenilin 1 can be prevented by a [[mutation]] that causes the loss of exon 9, and results in loss of function. Presenilins play a key role in the modulation of intracellular Ca<sup>2+</sup> involved in presynaptic  neurotransmitter release and long-term potentiation induction.<ref name="Zhang">{{cite journal |vauthors=Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, Südhof TC, Shen J | title = Presenilins are Essential for Regulating Neurotransmitter Release | journal = Nature | volume = 460 | issue = 7255 | pages = 632–6 |date=July 2009 | pmid = 19641596 | doi = 10.1038/nature08177 | url = | pmc = 2744588 }}</ref>

== Structure ==

The structure of [[PSEN1|presenilin-1]] is still controversial, although recent research has produced a more widely accepted model. When first discovered, the [[PSEN1]] gene was subjected to hydrophobicity analysis that predicted that the protein would contain ten trans-membrane domains. All previous models agreed that the first six putative membrane-spanning regions cross the membrane. These regions correspond to the N-terminal fragment of PS-1 but the structure of the C-terminal fragment was disputed. A recent paper by Spasic et al.<ref name="pmid16846981">{{cite journal |vauthors=Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W | title = Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway | journal = J. Biol. Chem. | volume = 281 | issue = 36 | pages = 26569–77 |date=September 2006 | pmid = 16846981 | doi = 10.1074/jbc.M600592200 | url =  }}</ref> provides strong evidence of a nine transmembrane structure with cleavage and assembly into the gamma-secretase [[Protein complex|complex]] prior to insertion into the [[plasma membrane]]. However, because this is a protein with large numbers of hydrophobic regions, it is unlikely that [[x-ray crystallography]] will provide definitive proof of the structure.

The structure of the presenilin-1 C-terminal catalytic fragment was determined using solution NMR.  It is made up of alpha helices and is 176 amino acids in length.<ref name=doetsch />  It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2).<ref>{{cite web|last1=Doetsch|first1=V.|title=2KR6: Solution structure of presenilin-1 CTF subunit|url=http://www.rcsb.org/pdb/explore/explore.do?structureId=2KR6|website=RCSB Protein Data Bank|accessdate=16 August 2016}}</ref>

== Function ==
Most cases of Alzheimer's disease are not hereditary. However, there is a small subset of cases that have an earlier age of onset and have a strong genetic element. In patients suffering from [[Alzheimer's disease]] ([[autosomal dominant]] hereditary), mutations in the presenilin [[protein]]s (PSEN1; PSEN2) or the [[amyloid precursor protein]] (APP) can be found. The majority of these cases carry mutant presenilin genes. An important part of the disease process in Alzheimer's disease is the accumulation of [[Amyloid beta]] (Aβ) protein. To form Aβ, APP must be cut by two [[enzymes]], [[beta secretase]]s and [[gamma secretase]]. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP.

Gamma secretase can cut APP at several points within a small region of the protein, which results in Aβ of various lengths. The lengths associated with Alzheimer's disease are 40 and 42 amino acids long. Aβ 42 is more likely to aggregate to form plaques in the brain than Aβ 40. Presenilin mutations lead to an increase in the ratio of Aβ 42 produced compared to Aβ 40, although the total quantity of Aβ produced remains constant.<ref name="pmid8986743">{{cite journal |vauthors=Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, Kholodenko D, Motter R, Sherrington R, Perry B, Yao H, Strome R, Lieberburg I, Rommens J, Kim S, Schenk D, Fraser P, St George Hyslop P, Selkoe DJ | title = Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice | journal = Nat. Med. | volume = 3 | issue = 1 | pages = 67–72 |date=January 1997 | pmid = 8986743 | doi = 10.1038/nm0197-67| url =  }}</ref> This can come about by various effects of the mutations upon gamma secretase.<ref name="pmid16405513">{{cite journal |vauthors=Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, Esselmann H, De Strooper B | title = Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms | journal = J. Neurochem. | volume = 96 | issue = 3 | pages = 732–42 |date=February 2006 | pmid = 16405513 | doi = 10.1111/j.1471-4159.2005.03578.x | url =  }}</ref> Presenilins are also implicated in the processing of [[Notch signaling|notch]], an important developmental protein. Mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted.<ref name="pmid9160754">{{cite journal |vauthors=Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S | title = Skeletal and CNS defects in Presenilin-1-deficient mice | journal = Cell | volume = 89 | issue = 4 | pages = 629–39 |date=May 1997 | pmid = 9160754 | doi = 10.1016/S0092-8674(00)80244-5| url =  }}</ref>

The genes for the presenilins were found through linkage studies using mutations present in familial Alzheimer's cases in 1995.<ref name="pmid7596406"/>

The genetic inactivation of presenilins in [[hippocampal]] synapses has shown this selectively affects the [[long-term potentiation]] caused by [[Theta rhythm|theta]] with the inactivation in presynapse but not the postsynapse impairing short-term plasticity and synaptic facilitation.<ref name="Zhang"/> The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca<sup>2+</sup> release.<ref name="Zhang"/> This has been suggested to "represent a general convergent mechanism leading to neurodegeneration".<ref name="Zhang"/>

==References==
{{Reflist|2}}

==External links==
* The [[MEROPS]] online database for peptidases and their inhibitors: Presenilin 1 [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A22.001 A22.001], Presenilin 2 [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=A22.002 A22.002]
* [http://www.dian-info.org Dominantly Inherited Alzheimer Network (DIAN)]
* [http://www.dianer.org Dominantly Inherited Alzheimer Network (DIAN) Expanded Registry]
* {{MeshName|Presenilins}}

{{Membrane proteins}}

[[Category:Moonlighting proteins]]