Presenilin

protein
Name=presenilin 1 (Alzheimer disease 3)
caption=


width=
HGNCid=9508
Symbol=PSEN1
AltSymbols=AD3
EntrezGene=5663
OMIM=104311
RefSeq=NM_000021
UniProt=P49768
PDB=
ECnumber=
Chromosome=14
Arm=q
Band=24.3
LocusSupplementaryData=protein
Name=presenilin 2 (Alzheimer disease 4)
caption=


width=
HGNCid=9509
Symbol=PSEN2
AltSymbols=AD4
EntrezGene=5664
OMIM=600759
RefSeq=NM_000447
UniProt=P49810
PDB=
ECnumber=
Chromosome=1
Arm=q
Band=31
LocusSupplementaryData=-q42

Presenilins are a family of related multi-pass transmembrane proteins that function as a part of the gamma-secretase protease complex. Vertebrates have two presenilin genes, 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). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm "C. elegans" has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1 [Smialowska, A.,Baumeister, R., Presenilin function in Caenorhabditis elegans, Neurodegenerative Diseases. Vol. 3(4-5)(pp 227-232), 2006.] .

Presenilins undergo cleavage in an alpha helical region of one of the cytoplasmic loops to produce a larger N-terminal and a smaller C-terminal fragment which together form part of the functional protein. Cleavage of presenilin 1 can be prevented by a mutation which causes the loss of exon 9, and results in loss of function.

Mutations in the presenilin proteins are known to cause early onset Alzheimer's disease through mechanisms which are still being elucidated.

tructure

The structure of 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 which 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. [Presenilin-1 maintains a nine transmembrane topology throughout the secretary pathway, Spasic D. et al. J. Biol. Chem., Vol. 281, Issue 36, 26569-26577, September 8, 2006] provides strong evidence of a nine trans-membrane structure with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. Unfortunately, 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.

Function

Most cases of Alzheimer's disease are not hereditary. However, there are 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 proteins (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 secretases and gamma secretase. Presenilin is the sub-component of gamma secretase that is responsible for the cutting of APP by gamma secretase.

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 alzheimers 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 [Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid β-protein in both transfected cells and transgenic mice, Citron M. et al. Nature medicine, vol 3, number 1, January 1997] . This can come about by various effects of the mutations upon gamma secretase [Presenilin clinical mutations can affect γ-secretase activity by different mechanisms, Bentahir M. et al. Journal of Neurochemistry (2006) 96, 732-742] .

Presenilins are also implicated in the processing of 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 [Skeletal and CNS defects in presenilin-1 deficient mice, Jie Shen et al. Cell, Vol. 89, 629–639, May 16, 1997] .

The genes for the presenilins were found through linkage studies using mutations present in familial alzheimer's cases in 1995 [Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease, Sherrington R. et al. Nature, Vol 375, 29 June 1995] .

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