Presenilin
Encyclopedia
Presenilins are a family of related multi-pass transmembrane proteins that function as a part 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 Prof Peter St George-Hyslop
at the Tanz Centre for Research in Neurodegenerative Diseases
at the University of Toronto
, and now also at the University of Cambridge
.
. 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). 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. Presenilins play a key role in the modulation of intracellular Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction.
Dominant mutations in the genes that encode presenilin proteins are the most common cause of familial early-onset Alzheimer's disease
.
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.
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. It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2). This information was found at the protein data bank
(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 secretases 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. 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.
The genetic 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+ release. This has been suggested to "represent a general convergent mechanism leading to neurodegeneratiom".
Intramembrane protease
Intramembrane proteases are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid...
complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's Disease by Prof Peter St George-Hyslop
Peter St George-Hyslop
Peter Henry St George-Hyslop, MD, FRS, FRSC, FRCPC, is a British and Canadian medical scientist, neurologist and molecular geneticist who is known for his research into neurodegenerative diseases...
at the Tanz Centre for Research in Neurodegenerative Diseases
Centre for Research in Neurodegenerative Diseases
The Tanz Centre for Research in Neurodegenerative Diseases is a research institute at the University of Toronto, under the umbrella of the Faculty of Medicine, with a focus on the spectrum of neurodegenerative diseases....
at the University of Toronto
University of Toronto
The University of Toronto is a public research university in Toronto, Ontario, Canada, situated on the grounds that surround Queen's Park. It was founded by royal charter in 1827 as King's College, the first institution of higher learning in Upper Canada...
, and now also at the University of Cambridge
University of Cambridge
The University of Cambridge is a public research university located in Cambridge, United Kingdom. It is the second-oldest university in both the United Kingdom and the English-speaking world , and the seventh-oldest globally...
.
. Vertebrates have two presenilin gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s, called PSEN1
PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
(located on chromosome 14 in humans) that encodes presenilin 1 (PS-1) and PSEN2
PSEN2
Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
(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
Caenorhabditis elegans
Caenorhabditis elegans is a free-living, transparent nematode , about 1 mm in length, which lives in temperate soil environments. Research into the molecular and developmental biology of C. elegans was begun in 1974 by Sydney Brenner and it has since been used extensively as a model...
has two genes that resemble the presenilins and appear to be functionally similar, sel-12
Sel-12
The Caenorhabditis elegans sel-12 gene encodes a multi-pass transmembrane domain protein that is similar to human presenilin. sel-12 positively regulates the lin-12 and glp-1 Notch signaling pathways during hermaphrodite gonadal, vulval, and germline development...
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
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
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 potentiation induction.
Dominant mutations in the genes that encode presenilin proteins are the most common cause of familial early-onset Alzheimer's disease
Alzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Structure
The structure of presenilin-1PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
is still controversial, although recent research has produced a more widely accepted model. When first discovered, the PSEN1
PSEN1
Presenilin-1 is a protein that in humans is encoded by the PSEN1 gene.- Function :Alzheimer's disease patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein...
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
Protein complex
A multiprotein complex is a group of two or more associated polypeptide chains. If the different polypeptide chains contain different protein domain, the resulting multiprotein complex can have multiple catalytic functions...
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
X-ray crystallography
X-ray crystallography is a method of determining the arrangement of atoms within a crystal, in which a beam of X-rays strikes a crystal and causes the beam of light to spread into many specific directions. From the angles and intensities of these diffracted beams, a crystallographer can produce a...
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. It was found that Alzheimer's patients carry mutations in the presenilin proteins (PSEN1; PSEN2). This information was found at the protein data bank
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 diseaseAlzheimer's disease
Alzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
(autosomal dominant hereditary), mutations in the presenilin protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s (PSEN1; PSEN2) or the amyloid precursor protein
Amyloid precursor protein
Amyloid precursor protein is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. Its primary function is not known, though it has been implicated as a regulator of synapse formation, neural plasticity and iron export...
(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
Amyloid beta
Amyloid beta is a peptide of 36–43 amino acids that is processed from the Amyloid precursor protein. While it is most commonly known in association with Alzheimer's disease, it does not exist specifically to cause disease...
(Aβ) protein. To form Aβ, APP must be cut by two enzymes, beta secretases and gamma secretase
Gamma secretase
Gamma secretase is a multi-subunit protease complex, itself an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases...
. 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. This can come about by various effects of the mutations upon gamma secretase. Presenilins are also implicated in the processing of notch
Notch signaling
The notch signaling pathway is a highly conserved cell signaling system present in most multicellular organisms.Notch is present in all metazoans, and mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass...
, 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.
The genetic inactivation of presenilins in hippocampal synapses has shown this selectively affects the long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
caused by theta
Theta rhythm
A theta rhythm is an oscillatory pattern in EEG signals recorded either from inside the brain or from electrodes glued to the scalp. Two types of theta rhythm have been described...
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+ release. This has been suggested to "represent a general convergent mechanism leading to neurodegeneratiom".
External links
- The MEROPSMeropsMerops may refer to:* Merops , a genus of bee-eaters.* MEROPS, an on-line database for peptidases.It may also refer to several figures from Greek mythology:* King of Ethiopia, husband of Clymene, who lay with Helios and bore Phaethon...
online database for peptidases and their inhibitors: Presenilin 1 A22.001, Presenilin 2 A22.002