Presenilin

Last updated
Presenilin
6idf psen1 notch blue asp.png
Cryo-electron microscopy structure of the human presenilin-1 (orange) in complex with a fragment of one of its protein substrates, Notch (green). The two catalytic sites are shown in blue. Rendered from PDB: 6IDF ​. [1]
Identifiers
SymbolPresenilin
Pfam PF01080
Pfam clan CL0130
InterPro IPR001108
MEROPS A22
TCDB 1.A.54
OPM superfamily 244
OPM protein 4hyg
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
presenilin 1
(Alzheimer's disease 3)
Identifiers
Symbol PSEN1
Alt. symbolsAD3
NCBI gene 5663
HGNC 9508
OMIM 104311
RefSeq NM_000021
UniProt P49768
Other data
EC number 3.4.23.-
Locus Chr. 14 q24.3
Search for
Structures Swiss-model
Domains InterPro
presenilin 2
(Alzheimer's disease 4)
Identifiers
Symbol PSEN2
Alt. symbolsAD4
NCBI gene 5664
HGNC 9509
OMIM 600759
RefSeq NM_000447
UniProt P49810
Other data
EC number 3.4.23.-
Locus Chr. 1 q31-q42
Search for
Structures Swiss-model
Domains InterPro

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. [2] Vertebrates have two presenilin genes, called PSEN1 (located on chromosome 14 in humans) that codes for presenilin 1 (PS-1) and PSEN2 (on chromosome 1 in humans) that codes for presenilin 2 (PS-2). [3] 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. [4]

Contents

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. [5] 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 Ca2+ involved in presynaptic neurotransmitter release and long-term potentiation induction. [6]

Structure

Presenilins are transmembrane proteins with nine alpha helices. Structures have been solved of the assembled gamma secretase complex by cryo-electron microscopy, demonstrating significant conformational flexibility in the structure of the presenilin subunit of the complex in response to ligand or inhibitor binding. [7] [1] Presenilins undergo autocatalytic proteolytic processing after expression, cleaving a cytoplasmic loop region between the sixth and seventh helices to produce a large N-terminal and a smaller C-terminal fragment. The two fragments remain in contact with each other in the mature protein. The two catalytic aspartate active site residues required for aspartyl protease activity are located in the sixth and seventh helices. [8]

The structure and membrane topology of presenilins was originally controversial when they were first discovered. The PSEN1 gene was predicted to contain ten trans-membrane domains; models agreed on the expected topology of the N-terminal fragment, but the structure of the C-terminal fragment was disputed. A 2006 study suggested a nine-pass transmembrane topology with cleavage and assembly into the gamma-secretase complex prior to insertion into the plasma membrane. [9] Solution NMR studies of the C-terminal fragment showed three helices likely to traverse the membrane, [5] [10] while X-ray crystallography studies of an archaeal homolog, [11] as well as cryo-electron microscopy of the human gamma-secretase complex, indicate nine transmembrane helices. [7] [1]

Function

Catalytic

Presenilins are the catalytic component of the gamma secretase intramembrane protease, a four-member protein complex consisting of presenilin, nicastrin, APH-1, and PEN-2. It has a very broad range of substrates for its proteolytic activity. Its substrates are hydrophobic single-pass transmembrane helices with relatively small extracellular regions. [12] [13] These substrates arise following ectodomain shedding. [13] Well over 100 different integral membrane proteins are processed by gamma-secretase. [8] The best-characterized gamma-secretase substrates are the Notch receptor and amyloid precursor protein (APP). [7] [13] Presenilins' role in the Notch signaling pathway is important in development; [14] mice that have the PS1 gene knocked out die early in development from developmental abnormalities similar to those found when notch is disrupted. [15] In conditional knockout mice where presenilin is only inactivated after early development, there is evidence that presenilins in their role as gamma-secretase components are important in the survival of neurons during aging. [14]

There are subtle and species-specific variations in the roles of presenilin-1 and presenilin-2 in assembled gamma-secretase complexes, with many studies suggesting a primary role for presenilin-1. [13] In humans, the two presenilins differ in subcellular localization, and may also be cell type and tissue-specific. [8]

Non-catalytic

Presenilins also have additional non-catalytic roles in other cellular signaling processes, including calcium homeostasis, lysosomal acidification, autophagy, and protein trafficking. [16] [17] [18] The proteins' role in calcium homeostasis in neurons has been a subject of interest. [19] 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. [6] The release of glutamate was also reduced in presynaptic terminals by processes that involve modulation of intracellular Ca2+ release. [6] This has been suggested to "represent a general convergent mechanism leading to neurodegeneration". [6]

Homologs have been identified and characterized in diverse eukaryotic organisms, including model organisms Drosophila melanogaster and Caenorhabditis elegans , plants such as Arabidopsis thaliana and Physcomitrella patens , and the slime mold Dictyostelium discoideum . [17] [18] In these functions presenilins are thought to play a role as scaffold proteins, considered likely to be the ancestral role of the protein family. [18]

Expression and distribution

Both human presenilins have widespread expression in the brain. The two proteins differ in subcellular localization, with PS1 expressed more broadly and present at the cell membrane, while PS2 is present mainly in late endosomes and lysosomes. [8] [20]

Association with Alzheimer's disease

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 with 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.

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. [21] This can come about by various effects of the mutations upon gamma secretase. [22]

Discovery

The genes for the presenilins were discovered in 1995 through linkage studies using mutations present in familial Alzheimer's disease cases. [2] Around the same time, the presenilin homolog in Caenorhabditis elegans , sel-12 , was independently identified as a contributor to Notch signaling. [23] Although the function of the protein products of these genes was not immediately apparent, it became clear from subsequent work that the mutations were associated with higher proportions of Aβ42 over the less amyloidogenic Aβ40. The role of presenilins as the catalytic component of the gamma secretase protein complex was established by the early 2000s. [24] [25]

Related Research Articles

<span class="mw-page-title-main">Notch signaling pathway</span> Series of molecular signals

The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of the amyloid beta (Aβ) protein mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. Abnormal neurites in amyloid plaques are tortuous, often swollen axons and dendrites. The neurites contain a variety of organelles and cellular debris, and many of them include characteristic paired helical filaments, the ultrastructural component of neurofibrillary tangles. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve with an average plaque area of 400-450 square micrometers (µm²). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. The apparent size of plaques is influenced by the type of stain used to detect them, and by the plane through which they are sectioned for analysis under the microscope. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid. Misfolded and aggregated Aβ is thought to be neurotoxic, especially in its oligomeric state.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span>

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons.

<span class="mw-page-title-main">Gamma secretase</span>

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. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Nicastrin</span>

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.

APH-1 is a protein gene product originally identified in the Notch signaling pathway in Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin. APH-1 homologs in other organisms, including humans, have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components.

<span class="mw-page-title-main">PEN-2</span> Protein-coding gene in the species Homo sapiens

PENSEN, formally PEN-2, is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">PSEN2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

Early-onset Alzheimer's disease (EOAD), also called Younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Notch proteins</span>

Notch proteins are a family of type-1 transmembrane proteins that form a core component of the Notch signaling pathway, which is highly conserved in metazoans. The Notch extracellular domain mediates interactions with DSL family ligands, allowing it to participate in juxtacrine signaling. The Notch intracellular domain acts as a transcriptional activator when in complex with CSL family transcription factors. Members of this Type 1 transmembrane protein family share several core structures, including an extracellular domain consisting of multiple epidermal growth factor (EGF)-like repeats and an intracellular domain transcriptional activation domain (TAD). Notch family members operate in a variety of different tissues and play a role in a variety of developmental processes by controlling cell fate decisions. Much of what is known about Notch function comes from studies done in Caenorhabditis elegans (C.elegans) and Drosophila melanogaster. Human homologs have also been identified, but details of Notch function and interactions with its ligands are not well known in this context.

<span class="mw-page-title-main">Protein pigeon homolog</span> Protein-coding gene in the species Homo sapiens

Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), 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 bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

<span class="mw-page-title-main">Rudolph E. Tanzi</span> American geneticist

Rudolph Emile 'Rudy' Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, Vice-chair of Neurology, Director of the Genetics and Aging Research Unit, and co-director of the Henry and Allison McCance Center for Brain Health at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since the 1980s when he participated in the first study that used genetic markers to find a disease gene. Dr. Tanzi co-discovered all three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson’s disease. As the leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer's families leading to the identification of novel AD candidate genes, including CD33 and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led to clinical trials at Prana Biotechnology. He is also working on gamma secretase modulators for the prevention and treatment of Alzheimer's. He also serves as Chair of the Cure Alzheimer's Fund Research Leadership Group and Director the Cure Alzheimer's Fund Alzheimer's Genome Project™.

<span class="mw-page-title-main">P3 peptide</span>

p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected of Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.

Alzheimer's disease (AD) in the Hispanic/Latino population is becoming a topic of interest in AD research as Hispanics and Latinos are disproportionately affected by Alzheimer's Disease and underrepresented in clinical research. AD is a neurodegenerative disease, characterized by the presence of amyloid-beta plaques and neurofibrillary tangles, that causes memory loss and cognitive decline in its patients. However, pathology and symptoms have been shown to manifest differently in Hispanic/Latinos, as different neuroinflammatory markers are expressed and cognitive decline is more pronounced. Additionally, there is a large genetic component of AD, with mutations in the amyloid precursor protein (APP), Apolipoprotein E APOE), presenilin 1 (PSEN1), bridging Integrator 1 (BIN1), SORL1, and Clusterin (CLU) genes increasing one's risk to develop the condition. However, research has shown these high-risk genes have a different effect on Hispanics and Latinos then they do in other racial and ethnic groups. Additionally, this population experiences higher rates of comorbidities, that increase their risk of developing AD. Hispanics and Latinos also face socioeconomic and cultural factors, such as low income and a language barrier, that affect their ability to engage in clinical trials and receive proper care.

References

  1. 1 2 3 Yang G, Zhou R, Zhou Q, Guo X, Yan C, Ke M, et al. (January 2019). "Structural basis of Notch recognition by human γ-secretase". Nature. 565 (7738): 192–197. doi:10.1038/s41586-018-0813-8. PMID   30598546. S2CID   57189683.
  2. 1 2 Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. (June 1995). "Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease". Nature. 375 (6534): 754–60. Bibcode:1995Natur.375..754S. doi:10.1038/375754a0. PMID   7596406. S2CID   4308372.
  3. ↑ Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, et al. (August 1995). "Candidate gene for the chromosome 1 familial Alzheimer's disease locus". Science. 269 (5226): 973–7. Bibcode:1995Sci...269..973L. doi:10.1126/science.7638622. PMID   7638622. S2CID   27296868.
  4. ↑ Smialowska A, Baumeister R (2006). "Presenilin function in Caenorhabditis elegans". Neuro-Degenerative Diseases. 3 (4–5): 227–32. doi:10.1159/000095260. PMID   17047361. S2CID   9695127.
  5. 1 2 Sobhanifar S, Schneider B, Löhr F, Gottstein D, Ikeya T, Mlynarczyk K, et al. (May 2010). "Structural investigation of the C-terminal catalytic fragment of presenilin 1". Proceedings of the National Academy of Sciences of the United States of America. 107 (21): 9644–9. Bibcode:2010PNAS..107.9644S. doi: 10.1073/pnas.1000778107 . PMC   2906861 . PMID   20445084.
  6. 1 2 3 4 Zhang C, Wu B, Beglopoulos V, Wines-Samuelson M, Zhang D, Dragatsis I, et al. (July 2009). "Presenilins are essential for regulating neurotransmitter release". Nature. 460 (7255): 632–6. Bibcode:2009Natur.460..632Z. doi:10.1038/nature08177. PMC   2744588 . PMID   19641596.
  7. 1 2 3 Bai XC, Rajendra E, Yang G, Shi Y, Scheres SH (December 2015). "Sampling the conformational space of the catalytic subunit of human γ-secretase". eLife. 4: e11182. doi: 10.7554/eLife.11182 . PMC   4718806 . PMID   26623517.
  8. 1 2 3 4 Güner G, Lichtenthaler SF (September 2020). "The substrate repertoire of γ-secretase/presenilin". Seminars in Cell & Developmental Biology. 105: 27–42. doi: 10.1016/j.semcdb.2020.05.019 . PMID   32616437.
  9. ↑ Spasic D, Tolia A, Dillen K, Baert V, De Strooper B, Vrijens S, Annaert W (September 2006). "Presenilin-1 maintains a nine-transmembrane topology throughout the secretory pathway". The Journal of Biological Chemistry. 281 (36): 26569–77. doi: 10.1074/jbc.M600592200 . PMID   16846981.
  10. ↑ PDB: 2KR6 ​; Doetsch V (2010). "Solution structure of presenilin-1 CTF subunit". Worldwide Protein Data Bank. doi:10.2210/pdb2kr6/pdb.
  11. ↑ Li X, Dang S, Yan C, Gong X, Wang J, Shi Y (January 2013). "Structure of a presenilin family intramembrane aspartate protease". Nature. 493 (7430): 56–61. Bibcode:2013Natur.493...56L. doi:10.1038/nature11801. PMID   23254940. S2CID   4429356.
  12. ↑ Struhl G, Adachi A (September 2000). "Requirements for presenilin-dependent cleavage of notch and other transmembrane proteins". Molecular Cell. 6 (3): 625–36. doi: 10.1016/S1097-2765(00)00061-7 . PMID   11030342.
  13. 1 2 3 4 Stanga S, Vrancx C, Tasiaux B, Marinangeli C, Karlström H, Kienlen-Campard P (February 2018). "Specificity of presenilin-1- and presenilin-2-dependent γ-secretases towards substrate processing". Journal of Cellular and Molecular Medicine. 22 (2): 823–833. doi: 10.1111/jcmm.13364 . PMC   5783875 . PMID   28994238.
  14. 1 2 Shen J (2 October 2013). "Function and dysfunction of presenilin". Neuro-Degenerative Diseases. 13 (2–3): 61–3. doi: 10.1159/000354971 . PMC   4000081 . PMID   24107444.
  15. ↑ Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S (May 1997). "Skeletal and CNS defects in Presenilin-1-deficient mice". Cell. 89 (4): 629–39. doi: 10.1016/S0092-8674(00)80244-5 . PMID   9160754. S2CID   8252011.
  16. ↑ Peric A, Annaert W (March 2015). "Early etiology of Alzheimer's disease: tipping the balance toward autophagy or endosomal dysfunction?". Acta Neuropathologica. 129 (3): 363–81. doi: 10.1007/s00401-014-1379-7 . PMC   4331606 . PMID   25556159.
  17. 1 2 Duggan SP, McCarthy JV (January 2016). "Beyond γ-secretase activity: The multifunctional nature of presenilins in cell signalling pathways". Cellular Signalling. 28 (1): 1–11. doi:10.1016/j.cellsig.2015.10.006. PMID   26498858.
  18. 1 2 3 Otto GP, Sharma D, Williams RS (April 2016). "Non-Catalytic Roles of Presenilin Throughout Evolution". Journal of Alzheimer's Disease. 52 (4): 1177–87. doi: 10.3233/JAD-150940 . PMC   4927835 . PMID   27079701.
  19. ↑ Honarnejad K, Herms J (November 2012). "Presenilins: role in calcium homeostasis". The International Journal of Biochemistry & Cell Biology. 44 (11): 1983–6. doi:10.1016/j.biocel.2012.07.019. PMID   22842534.
  20. ↑ Barthet G, Mulle C (November 2020). "Presynaptic failure in Alzheimer's disease" (PDF). Progress in Neurobiology. 194: 101801. doi:10.1016/j.pneurobio.2020.101801. PMID   32428558. S2CID   218655934.
  21. ↑ Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, et al. (January 1997). "Mutant presenilins of Alzheimer's disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice". Nature Medicine. 3 (1): 67–72. doi:10.1038/nm0197-67. PMID   8986743. S2CID   10834438.
  22. ↑ Bentahir M, Nyabi O, Verhamme J, Tolia A, Horré K, Wiltfang J, et al. (February 2006). "Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms". Journal of Neurochemistry. 96 (3): 732–42. doi: 10.1111/j.1471-4159.2005.03578.x . PMID   16405513.
  23. ↑ Levitan D, Greenwald I (September 1995). "Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene". Nature. 377 (6547): 351–4. Bibcode:1995Natur.377..351L. doi:10.1038/377351a0. PMID   7566091. S2CID   4314257.
  24. ↑ De Strooper B, Iwatsubo T, Wolfe MS (January 2012). "Presenilins and γ-secretase: structure, function, and role in Alzheimer Disease". Cold Spring Harbor Perspectives in Medicine. 2 (1): a006304. doi: 10.1101/cshperspect.a006304 . PMC   3253024 . PMID   22315713.
  25. ↑ Wolfe MS (February 2007). "When loss is gain: reduced presenilin proteolytic function leads to increased Abeta42/Abeta40. Talking Point on the role of presenilin mutations in Alzheimer disease". EMBO Reports. 8 (2): 136–40. doi:10.1038/sj.embor.7400896. PMC   1796780 . PMID   17268504.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.