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.
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. Presenilins play
a key role in the modulation of intracellular Ca2+
involved in presynaptic neurotransmitter release and long-term
Mutations in the presenilin proteins are known to cause early
onset Alzheimer's disease.
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.
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.
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. 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.
for the presenilins were found through linkage studies using mutations
present in familial Alzheimer's cases in 1995.
inactivation of presenilins in hippocampal synapses has shown
this selectively affects the long-term potentiation caused by
theta with the inactivation in presynapse but not the postsynapse
impairing short-term plasticity and synaptic facilitation.
The release of glutamate was also reduced in presynaptic terminals
by processes that involve modulation of intracellular Ca2+
has been suggested to "represent a general convergent mechanism
leading to neurodegeneratiom".
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