Presenilin

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.

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.

Structure

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. 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. This can come about by various effects of the mutations upon gamma secretase.

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.

The genes for the presenilins were found through linkage studies using mutations present in familial alzheimer's cases in 1995 .

References

External links