|
 
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| ORIGINAL ARTICLE |
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| Year : 2021 | Volume
: 8
| Issue : 3 | Page : 179-190 |
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In silico characterization of predominant genes involved in early onset of alzheimer's disease
Punya Sachdeva1, Faizan Ahmad2
1 Amity Institute of Neuropsychology and Neurosciences, Amity University, Uttar Pradesh, Noida, India
2 Department of Medical Elementology and Toxicology, Jamia Hamdard University, Delhi, India
| Date of Submission | 15-Jul-2021 |
| Date of Decision | 12-Nov-2021 |
| Date of Acceptance | 19-Nov-2021 |
| Date of Web Publication | 27-Dec-2021 |
Correspondence Address:
Punya Sachdeva
Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, Uttar Pradesh
India
 Source of Support: None, Conflict of Interest: None
DOI: 10.4103/jnbs.jnbs_34_21
Objective: Alzheimer's disease (AD) is a predominant neurodegenerative disorder and one of the most prevalent forms of dementia, affecting 35 million people worldwide. The neuropathologic characteristics of this disorder show extracellular aggregation of amyloid plaques composed of amyloid-beta (Aβ) peptides and the presence of hyperphosphorylated tau protein leading to the formation of neurofibrillary tangle inside the neurons. Some of the significant clinical presentations of AD patients include memory decline, trouble in speech, personality alterations, gait imbalance, and mood changes. A tremendous core of genetics is involved in the prevalence of AD. The three vital genes such as amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) have a definite association with AD. The objective of this study was to characterize these genes, which are immensely relevant in health-care practices and the formation of personalized medications. Materials and Methods: The characterization of genes has been done using several databases such as the National Center for Biotechnology Information, GeneCards, Human Protein Atlas, tissue expression database, and protein modeling server – Swiss-model. Results: As a result, we got the genomic and subcellular location of genes. Furthermore, we got the expression concentration of proteins in tissues, three-dimensional protein structures using amino acid sequences, string connection with various proteins, features of genes, and the protein encoded by it. Conclusion: We reach the conclusion that protein expression of APP is high in the brain, spinal canal, liver, lungs, and small and large intestine. PSEN1 concentration of expression is high in the brain and spinal, whereas PSEN2 concentration of expression is high in the liver, lungs, brain, and intestine.
Keywords: Alzheimer's disease, amyloid precursor protein, PSEN1, PSEN2
How to cite this article:
Sachdeva P, Ahmad F. In silico characterization of predominant genes involved in early onset of alzheimer's disease. J Neurobehav Sci 2021;8:179-90 |
How to cite this URL:
Sachdeva P, Ahmad F. In silico characterization of predominant genes involved in early onset of alzheimer's disease. J Neurobehav Sci [serial online] 2021 [cited 2022 May 26];8:179-90. Available from: http://www.jnbsjournal.com/text.asp?2021/8/3/179/333760 |
| Introduction | |  |
Alzheimer's disease (AD) is the most prominent form of dementia, affecting 30 million people worldwide.[1] If symptoms come into sight to the people within the age group of 30–65 years, then it is termed early-onset AD (EOAD) or late-onset AD (LOAD when symptoms appear after 65 years of age.[2],[3] Characteristic clinical presentation of AD is memory impairment, language difficulty, personality, and behavioral variations. About 25% of EOAD subjects show the nonmemory phenotype. Neuropathologic signs of an AD brain consist of amyloid plaque deposits formed extracellularly by amyloid-beta (Aβ) peptide from amyloid-beta precursor protein and accumulation of hyperphosphorylated tau protein leading to the formation of neurofibrillary tangles (NFTs) inside the nerve cells, intruding the neuronal network.[4],[5],[6] There are several risk factors associated with AD, such as familial inheritance, aluminum toxicity due to high aluminum exposure, infection, vascular diseases, traumatic brain injury, and diet.[7] Although high amyloid has been linked with strong episodic memory deterioration over 18 and 36 months in fit older adults and people with medium cognitive impairment. However, the kind and quantity of memory related to amyloid and nonmemory switch from the preclinical to the clinical degrees of AD has not been assessed over the time interval.[8] Despite the important public health concern that it postures, only five medical approaches have been licensed for AD, and these documents to manage symptoms rather than change the development of the disease. Studies of potential disease-modifying treatment have usually been tried in patients with the clinically detectable disease, yet data imply that the pathological alterations connected with AD start numerous years before this. Pharmacological treatment may be helpful in this preclinical step before the neurodegenerative process is placed.[9],[10],[11] In 1907, Alois Alzheimer, a pronounced German neuropathologist and psychiatrist, performed an autopsy on a 55-year-old lady named Auguste Deter, who died of a critical cognitive disorder.[12],[13],[14],[15] Alois Alzheimer saw abnormal intracellular accumulation during the process of necropsy, which was later defined as NFT's and the presence of “Miliary Foci” extracellularly now reported as neuritic plaques. In 1984, Wong and his colleague named Glenner isolated the neuritic plaque and described it as a fragment of 40–42 amino acids and 4.2 kDa peptide that is cleaved from a precursor protein. To extend their research, they cloned the neuritic plaque and named it an Amyloid-beta peptide. Further, Roth and Tomlinson (Father of AD Neuropathology) concluded that Aβ peptide upraises the risk of dementia in elderly people.[16],[17],[18],[19] In Youn 2014 et al.'s study, γ-linolenic acid was discovered as a novel BACE1 specific inhibitor.[20] In Dhananjayan 2014 et al.'s study, in silico docking studies, it revealed that targeting BACE1 inhibition through Polyphenolic compounds can create a number of lead molecules for better therapeutic concern in future.[21] Khan 2012 et al. revealed that PDB ID: 3MOQ shares query coverage 78% and maximum identity 96% to a hypothetical protein of AD. Validation of structure was done by using PROCHECK available at SAVES server. The validated model is submitted in PMDB (i.e., ID: PM0078182). The predicted model of amyloid precursor protein (APP) can be further used for drug target identification.[22]
Genetic etiology of Alzheimer's disease
There is the involvement of multiple genes associated with AD, such as phospholipase D family member 3, triggering receptor expressed on myeloid cells 2, apolipoprotein E (APOE4), ATP binding cassette subfamily A member 7 (ABCA7) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), bridging integrator 1 (BIN1), cas scaffold protein family member 4 (CASS4), and cas scaffold protein family member 4 (CASS4) genes.[23],[24],[25],[26] Heritability is high varying from 92% to 100% in EOAD patients as compared to LOAD patients which stretch from 70% to 80% only.[27] Based on monogenic pedigree analysis, it was identified that three major genes coding for APP, presenilin-1 (PSEN1), and presenilin-2 (PSEN2) can be involved in patients with AD.[28],[29],[30],[31] Besides, another trial was continued to recognize genes for inherited AD by isolating Aβ peptide from vessels of people with Down syndrome (DS), caused by trisomy 21, and form plaques of AD patient's brain revealed nearly strong homology between the two diseases. Indicating there is a standard genetic framework associated with chromosome 21q, from autosomal dominant families.[32],[33] 119 probands were taken in which 52 mutations were detected in the APP gene. In general, the mutations were nonsynonymous, but missense mutation was also inscribed. The most often mutated gene in AD was PSEN1,[20] it showed 215 mutations in 475 probands and 31 mutations were detected in the PSEN2 gene in 24 probands.[34],[36] [Table 1] Shows the characteristics of APP, PSEN1 and PSEN2 has been shown in [Figure 1] | Figure 1: The genomic location of amyloid precursor protein gene which is on long arm (q), chromosome number 21, at position 21.1-21.3 in red-colored mark
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 | Table 1: The classification of Amyloid precursor protein, Presenilin- and Presenilin-2 genes
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| Materials and Methods | | |
There is no need for ethics committee approval. The databases for the completion of this study were National Center for Biotechnology (NCBI), PubMed, Swiss-model, Ensembl, GeneCards, OMIM, UniPort, HUGO Gene Nomenclature Committee, Protein Data Bank, etc., Moreover, to keep all referred articles, images, and data in an organized manner, we made use of Benchling which is an electronic digital notebook. This notebook helped me to stay on track during this study. The detailed information of some databases and the procedure has been discussed below:
PubMed
It is the main search engine which we used to collect the required information. We looked for APP, AD, PSEN1, and PSEN2.
National Center for Biotechnology Information
From NCBI, we collected genomic, mRNA, and amino acid sequences of APP, PSEN1, and PSEN2 genes. This tool is very important to analyze genomic data or molecular data. The amino acid length I chose for APP is 770, for PSEN1 is 562, and for PSEN2, it was 566 and took a sequence of 1000 base pairs only, and then, “FASTA” was used to save the nucleotide sequence.
GeneCards
This is a database used to search for human genes. It provides information regarding any gene. This database has sections to understand a gene alias, disorders, expression, localization, orthologs, functions, drugs, proteins, transcripts, variants, etc., In our study, we gathered information such as symbol, protein, synonym, and organism using GeneCards.
Swiss-model
This is a protein modeling server, which provides us with 3D structures of proteins for analysis. It has different templates and summaries for the structure of our protein. We gathered three protein structures for APP, PSEN1, and PSEN2 genes. It helps us to change the theme of the protein and allows us to download it for further reference. I also downloaded the Ramachandran plot for all three proteins. The detailed information can also be accessed using this database such as QMEAN, protein classification, GMQE, oligo state, and peptide. The Ramachandran Plot for PSEN2 has been shown in [Figure 16]. | Figure 16: The Ramachandran plot for presenilin-2 amino acid residues. The cluster of dots in the plot suggests that the protein has right-handed alpha-helix or anti-parallel beta-sheet structure
Click here to view |
Ensembl gene browser
This is a database notably beneficial to collect data on genomic sequences, transcriptional sequences, sequence variation, etc., In our study, we collected data of description, gene synonyms, transcripts, chromosome location, orthologues, paralogues, and the phenotype associated with APP, PSEN1, and PSEN2 genes. More specifically, we used Ensembl Version ENSG00000142192.21 to collect information.
Benchling
This is a digital electronic notebook. This platform makes it remarkably clear to share collected data, experiment report, or information with other scientists. This digital notebook is very essential for sequence designing, documenting information regarding projects, data acquisition, reporting, etc., To proceed with any task, we must have proper formatting and theoretical plans for that, Benchling provides a very well-defined space to carry our research work.
| Results | | |
Features of amyloid precursor protein, PSEN1, and PSEN2 Gene
These three genes play a crucial role in onset of AD, the information regarding these genes has been collected from databases such as, Ensembl, UniPort, and GeneCards.
| Discussion | | |
Characterization of amyloid precursor protein gene
APP gene encodes for amyloid-beta precursor protein. This protein is a surface receptor and transmembrane protein that can be cleaved into various peptides by secretases. The two peptides for this protein show bactericidal and antifungal activities.[35],[36]
Subcellular localization of amyloid precursor protein gene
In the maturation phase, the immature APP moves to the Golgi apparatus, where the maturation takes place. The soluble APP released after the action of alpha-secretase in the extracellular space. Some portion of APP also gets accumulated in the secretory transport vesicles and returns to the cell surface. APP is mainly in the Golgi apparatus.
Characterization of amyloid precursor protein
Human APP is a transmembrane protein that performs a significant function in the central nervous system. The cleavage of this protein by the γ-secretase enzyme releases a large extracellular domain known as secreted APP alpha. APP can also be cleaved to Aβ peptide in a proteolytic process; if there is the involvement of the β-secretase enzyme, it will cleave the APP in such a way that a nonsoluble peptide is formed known as amyloid β (Aβ) peptide. This peptide accumulates in the brain extracellularly and intrudes the neuronal network, which is one of the primary characteristic features in the Onset of AD.[36],[37]
Analysis of amyloid precursor protein structure
Amyloid precursor protein genomic location has been shown in [Figure 1], the subcellular localization has been shown in [Figure 2]. Further the Ramachandran plot has been explained in [Figure 4] and protein-protein interaction mesh like structure takne from database string has been shown in [Figure 5]. | Figure 2: The subcellular localization of amyloid precursor protein gene from the compartments. The concentration is high in plasma membrane, extracellular, mitochondrion, nucleus, endoplasmic reticulum, endosome, cytosol, and Golgi apparatus. Combined confidence scores of the localization confirmation are selected based on evidence type and source and envisioned both in a table and in the schematic cell representation. The confidence scale is color coded, extending from light green color (1) for low confidence to dark green color (5) for high confidence. White color (0) indicates a lack of localization evidence
Click here to view |
 | Figure 4: The Ramachandran plot for amyloid precursor protein amino acid residues. The cluster of dots in the plot suggests that the protein is making right-handed alpha-helix structure
Click here to view |
 | Figure 5: The protein interactions string of amyloid precursor protein (APP). The proteins which are involved in interaction are presenilin-1 (PSEN1), amyloid-betta A4 precursor protein-binding family A member 1 (APBA1), alpha-synuclein (SNCA), amyloid-beta A4 precursor protein-binding family B member 1 (APBB1), apolipoprotein-E (APOE), A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), beta-site APP cleaving enzyme-1 (BACE1), sortilin-related receptor (SORL1), clusterin (CLU), and integral membrane protein 2B (ITM2B)
Click here to view |
Ramachandran plot of amyloid precursor protein
Ramachandran plot predicts the secondary structures of protein by the amino acid residues. Each amino acid has two backbone bonds that can rotate which sets the dihedral angles (φ and ψ). The peptide is not able to rotate because of the presence of a partial double bond. This plot is of torsional angles, where on x-axis, the values of φ are taken and on y-axis, values of ψ are taken.
Details of amyloid precursor protein structure
The details of the APP have been extracted from a protein modeling server – Swiss-model.
Amino acid sequence of amyloid precursor protein
The functionality and structure of a protein is determined by its amino acid residues. The amino acid sequence for APP was extracted from database Ensembl, which has been type-written below.
MLPGLALLLLAAWTARALEVPTDGNAGLL AEPQIAMFCGRLNMHMNVQNGKWDSDPS GTKTCIDTKEGILQYCQEVYPELQITNVVE ANQPVTIQNWCKRGRKQCKTHPHFVIPYR CLVGEFVSDALLVPDKCKFLHQERMDVCE THLHWHTVAKETCSEKSTNLHDYGMLLPC GIDKFRGVEFVCCPLAEESDNVDSADAEED DSDVWWGGADTDYADGSEDKVVEVAEEEE VAEVEEEEADDDEDDEDGDEVEEEAEEPYEE ATERTTSIATTTTTTTESVEEVVREVCSEQAET GPCRAMISRWYFDVTEGKCAPFFYGGCGGNRN NFDTEEYCMAVCGSAMSQSLLKTTQEPLARDP VKLPTTAASTPDAVDKYLETPGDENEHAHFQK AKERLEAKHRERMSQVMREWEEAERQAKNLP KADKKAVIQHFQEKVESLEQEAANERQQLVET HMARVEAMLNDRRRLALENYITALQAVPPRPRH VFNMLKKYVRAEQKDRQHTLKHFEHVRMVDP KKAAQIRSQVMTHLRVIYERMNQSLSLLYNVPA VAEEIQDEVDELLQKEQNYSDDVLANMISEPRIS YGNDALMPSLTETKTTVELLPVNGEFSLDDLQP WHSFGADSVPANTENEVEPVDARPAADRGLTT RPGSGLTNIKTEEISEVKMDAEFRHDSGYEVHHQ KLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLV MLKKKQYTSIHHGVVEVDAAVTPEERHLSKMQ QNGYENPTYKFFEQMQ
Chemical properties of amyloid precursor protein
The details of amyloid precursor protein 3-Expression of amyloid precursor protein in tissues D protein structure has been shown in [Table 2] and The chemical properties of amyloid precursor protein of 770 amino acid residues has been shown in [Table 3]. | Table 3: The chemical properties of amyloid precursor protein of 770 amino acid residues
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String interactants of amyloid precursor protein
The string interacts of APP has been collected from String interaction database. It shows the possible protein–-protein interaction.
Expression of amyloid precursor protein in tissues
The expression concentration of APP in tissues and organs has been shown in [Figure 6]. | Figure 6: The concentration of expression of amyloid precursor protein (APP) in human body organs. The confidence scale extends from 0 (low concentration) to 5 (high concentration). The higher the concentration of APP in a specific tissue, the more will the number (0–5) in the confidence scale, and the darker will be green color of that organ in the figure, like brain, spinal canal, liver, lungs, and small and large intestine shows a high concentration of APP. The tissue associations are acquired from curated (Professional) information in UniProtKB manually. The confidence of individual association is implied by stars, where ★★★★★ is the most extraordinary confidence and ★☆☆☆☆ is the weakest
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Characterization of PSEN1 gene
This is a protein-coding gene which encodes for presenilin-1 (PS-1) protein. This gene has 25 transcripts, 198 orthologues, 2 paralogues, and 11 phenotypes associated with it. It is involved in presenilin-mediated signaling pathway and neurogenerative pathway. This molecular function of PS-1 is of hydrolase and protease.[37],[38],[39]
Subcellular Location of PSEN1 gene
The genomic location of PSEN1 has been shown in [Figure 7] and the detailed view of Subcellular Location of the gene is shown in [Figure 8]. | Figure 7: The location of gene physically on a chromosome (Genomic Location) of PSEN1 gene on long arm (q) of chromosome number 14 at position 24.2 in red coloured mark
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 | Figure 8: The localization od PSEN1 gene in the subcellular compartments. It has been detected that localization of PSEN1 gene is high in Golgi apparatus (Main Location), nucleoplasm and cell junction (additional location). Confidence scale is colour extending from light green showing low confidence to dark green showing high confidence
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Characterization of presenili-1 (PS-1)
The presenilin-1 (PS-1) is an integral transmembrane protein encoded by PSEN-1 gene present on chromosome 14 (14q24.3). It is a protein of 467 amino acids and the molecular weight is 57 kDa. This protein is present in the gamma-secretase complex and helps in the processing of APP. This also helps in formation of amyloid-beta peptide, responsible for pathogenesis in AD. It facilitates multiple biological functions, but more specifically, if we talk about the brain, it helps in cerebral cortex cell migration, astrocyte activation, cerebellum development, brain morphogenesis, memory and learning, and dorsal and ventral neural tube formation.[40]
Analysis of presenilin-1 structure
The detailed view of Analysis of amyloid precursor protein structure is shown in [Figure 3]. | Figure 3: The three-dimensional structure of amyloid precursor protein in “Ball and Stick” molecular model. The “spheres” show the atoms of various amino acids and their bonds with other atoms are shown by “sticks.” The presence of chemical elements of every atom is presented by different colors in the structure. The spheres of color turquoise blue indicate various amino acids such as leucine (Leu), phenylalanine (Phe), glutamic acid (Glu), lysine (Lys), Histidine (His), Serine (Ser), Tyrosine (Tyr), Proline (Pro), Glutamine (Gln), aspartic acid (Asp), alanine (Ala), and methionine (Met). The red-colored spheres indicate a ligand 2-deoxy-6-O-sulfo-2-(sulfoamino)-alpha-D-glucopyranose (SGN), whereas yellow colored sphere indicates a ligand 2-O-sulfo-alpha-L-idopyranuronic acid (IDS)
Click here to view |
Ramachandran plot for presenili-1
Ramachandran plot predicts the secondary structures of protein by the amino acid residues. Each amino acid has two backbone bonds that can rotate which sets the dihedral angles (φ and ψ). The peptide is not able to rotate because of the presence of a partial double bond. This plot is of torsional angles, where on x-axis, the values of φ are taken and on y-Axis, values of ψ are taken.
Details of PSEN1 protein structure
Details of PSEN1 protein structure is shown in [Figure 9] and Ramachandran plot for presenilin 1 has been shown in [Figure 10], the string connection has been shown in [Figure 11]. | Figure 9: This is the three-dimensional structure of Presenilin-1. It is in “Ball and Stick” molecular model, where the ball represents atoms connected with other atoms by covalent bond which is shown by sticks. The different colors in the structure represent presence of multiple types of amino acids such as proline (Pro), methionine (Met), cysteine (Cys), histidine (His), alanine (Ala), threonine (Thr), tyrosine (Tyr), valine (Val), isoleucine (Ile), phenylalanine (Phe), lysine (Lys), glycine (Gly), serine (Ser), glutamic acid (Glu), aspartic acid (Asp), leucine (Leu), and asparagine (Asn)
Click here to view |
 | Figure 10: The Ramachandran plot for presenilin-1 amino acid residues. The cluster of dots in the plot suggests that the protein has right-handed alpha-helix or anti-parallel beta-sheet structure
Click here to view |
 | Figure 11: The protein interaction of presenilin-1. The proteins which are involved in interactions are amyloid precursor protein (APP), presenilin enhancer, gamma-secretase subunit (PSENEN), neurogenic locus notch homolog protein 3 (NOTCH3), neurogenic locus notch homolog protein 2 (NOTCH2), neurogenic locus notch homolog protein 1 (NOTCH1), nicastrin (NCSTN), aph-1 homolog B, gamma-secretase subunit (APH 1B), aph-1 homolog A, gamma-secretase subunit (APH 1A), presenilin-2 (PSEN2) and catenin beta-1 (CTNNB1)
Click here to view |
Amino acid sequence for presenili-1
The functionality and structure of a protein is determined by its amino acid residues. The amino acid sequence for presenilin-1 (PSEN1) was extracted from database Ensembl, which has been type-written below:
MTELPAPLSYFQNAQMSEDNHLSNTVRSQND NRERQEHNDRRSLGHPEPLSNGRPQGNSRQV VEQDEEEDEELTLKYGAKHVIMLFVPVTLCM VVVVATIKSVSFYTRKDGQLIYTPFTEDTETV GQRALHSILNAAIMISVIVVMTILLVVLYKYR CYKVIHAWLIISSLLLLFFFSFIYLGEVFKTYN VAVDYITVALLIWNFGVVGMISIHWKGPLRL QQAYLIMISALMALVFIKYLPEWTAWLILAV ISVYDLVAVLCPKGPLRMLVETAQERNETLF PALIYSSTMVWLVNMAEGDPEAQRRVSKNSK YNAESTERESQDTVAENDDGGFSEEWEAQRD SHLGPHRSTPESRAAVQELSSSILAGEDPEERGV KLGLGDFIFYSVLVGKASATASGDWNTTIACFV AILIGLCLTLLLLAIFKKALPALPISITFGLVFYFA TDYLVQPFMDQLAFHQFYI.
Chemical properties of Presenili-1
The details pf PSEN1 has been shown in [Table 4] and The chemical properties of of PSEN1 has been shown in [Table 5]. | Table 4: The details of PS-1, the protein up of is made four similar subunits (Hetero tetramer)
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 | Table 5: The chemical properties of Presenilin-1 of 467 amino acid residues
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Protein interacts of PSEN1
The string interacts of PSEN1 has been collected from String interaction database. It shows the possible protein–protein interaction.
Expression of PSEN1 in tissues
The genomic location of PSEN2 has been given on [Figure 13]. The in [Table 7] expression concentration of PSEN1 has been shown in [Figure 12]. | Figure 13: The Location of gene physically on a chromosome (Genomic Location) of PSEN2 gene on long arm (q) of chromosome number 14 at position 42.13 in red coloured mark
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 | Table 7: The chemical properties of Presenilin-2 of 471 amino acid residues
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 | Figure 12: The concentration of expression of PSEN1 in human body organs. The confidence scale extends from 0 (low concentration) to 5 (high concentration). The higher the concentration of PSEN1 in a specific tissue, the more will the number (0-5) in the confidence scale, and the darker will be green color of that organ in the figure, such as brain and spinal canal show the highest concentration of PSEN1. The tissue associations are acquired from curated information in UniProtKB manually. The confidence of individual association is implied by stars, where ★★★★★ is the most extraordinary confidence and ★☆☆☆☆ is the weakest
Click here to view |
Characterization of PSEN2 gene
The gene encoding for a presenilin-2 protein is located on chromosome 1. It is a transmembrane protein located intracellularly. The molecular weight of PSEN-2 is 55 kDa. This protein has 448 amino acids. The function involves transferring the chemical signals from the membrane of the cell to the nucleus, inside the nucleus this protein will serve to stimulate certain genes which are responsible for cellular maturation and growth.[41]
Subcellular localization of PSEN2 gene
The subcellular localization of PSEN2 gene has been shown in [Figure 14]. | Figure 14: The subcellular localization of gene from compartments. The PSEN2 gene is mainly localized in the nucleoplasm, plasma membrane, cytoskeleton and nucleus All the rest compartments are non-detected. Collected confidence grade of the localization confirmation are selected based on evidence type and source and envisioned both in a table and in the schematic cell representation. The confidence scale is colour coded, extending from low confidence (1) shown in light green to high confidence (5) shown in dark green
Click here to view |
Characterization of presenilin-2
The gene encoding for a presenilin-2 Protein is positioned on chromosome 1. It is a transmembrane protein located intracellularly. The molecular weight of PSEN-2 is 55 kDa. The presenilin-2 is a stretch of 448 amino acids. The function involves transferring the chemical signals from the membrane of the cell to the nucleus; inside the nucleus, this protein will serve to stimulate certain genes which are responsible for cellular maturation and growth. Presenilin-2 is a subunit that participates in the cleavage of APP; during this process, it can produce Aβ peptides of multiple lengths. The aggregation of Aβ peptide (Aβ42) is the main hallmark in the brains of AD patients. Numerous studies have shown that AD-related presenilin mutations can change intracellular calcium signaling, which directs to Aβ accumulation to form neuritic plaques and cause the loss of neurons.[42]
Analysis of presenili-2 structure
The analysis of 3D model of PSEN2 protein structure modelled from swiss model has been shown in [Figure 15] and the The Ramachandran plot for presenilin-2 is shown in [Figure 17]. | Figure 15: This is the 3-dimensional structure of Presenilin-2. It is in 'Ball and Stick' molecular model, where the ball represents Atoms connected with other atoms by covalent bond which is shown by sticks. The different colors in the structure represent presence of multiple types of amino acids such as proline (Pro), methionine (Met), cysteine (Cys), alanine (Ala), threonine (Thr), tyrosine (Tyr), valine (Val), phenylalanine (Phe), lysine (Lys), glycine (Gly), serine (Ser), glutamic acid (Glu), aspartic acid (Asp), leucine (Leu), asparagine (Asn), arginine (Arg), etc
Click here to view |
 | Figure 17: The protein interaction of Presenilin-2. The protein which are involved in interactions are Amyloid Precursor Protein (APP), Presenilin Enhancer, Gamma-Secretase Subunit (PSENEN), Neurogenic locus notch homolog protein 3 (NOTCH3), Neurogenic locus notch homolog protein 4 (NOTCH4) Neurogenic locus notch homolog protein 2 (NOTCH2), Neurogenic locus notch homolog protein 1 (NOTCH1), Nicastrin (NCSTN), Aph-1 Homolog B, Gamma-Secretase Subunit (APH 1B), Aph-1 Homolog A, Gamma-Secretase Subunit (APH 1A) and Presenilin-1 (PSEN1)
Click here to view |
Ramachandran plot for PSEN2
Ramachandran plot predicts the secondary structures of protein by the amino acid residues. Each amino acid has two backbone bonds that can rotate which sets the dihedral angles (φ and ψ). The peptide is not able to rotate because of the partial double bond. This plot is of torsional angles, where on x-axis, the values of Phi φ are taken, and on y-axis, values of Psi ψ are taken.
Details of presenilin-2
The details of PSEN2 has been shown in [Table 6] and the chemical properties of Presenilin-2 of 471 amino acid residueshas been shown in [Figure 7]. | Table 6: The details of PS-2, the protein up of is made four similar subunits (Monomer)
Click here to view |
{Figure 7}
Amino acid sequence of Presenilin-2
MLTFMASDSEEEVCDERTSLMSAESP TPRSCQEGRQGPEDGENTAQWRSQEN EEDGEEDPDRYVCSGVPGRPPGLEEEL TLKYGAKHVIMLFVPVTLCMIVVVATIK NSVLNTLIMISVIVVMTIFLVVLYKYRCY KFIHGWLIMSSLMLLFLFTYIYLGEVLKT YNVAMDYPTLLLTVWNFGAVGMVCIHW KGPLVLQQAYLIMISALMALVFIKYLPEWS AWVILGAISVYDLVAVLCPKGPLRMLVETA QERNEPIFPALIYSSAMVWTVGMAKLDPSS QGALQLPYDPEMEEDSYDSFGEPSYPEVFEP PLTGYPGEELEEEEERGVKLGLGDFIFYSVLV GKAAATGSGDWNTTLACFVAILIMASHSCCP GWSAMVRFGSLWPLPPGFKRFSCLSLPYQFNF FRFHVHTAGGHLPDSPAASCGYVIEGQPVKR GQK
Chemical properties of presenilin-2
The chemical properties of PSEN2 has been shown.
Protein string interactants of PSEN2
The string interacts of PSEN2 have been collected from String interaction database. It shows the possible protein–protein interaction.
Expression of PSEN2 in tissues
The tissue expression of PSEN2 has been shown in [Figure 18]. | Figure 18: The concentration of expression of PSEN2 in human body organs. The confidence scale extends from 0 (low concentration) to 5 (high concentration). The higher the concentration of PSEN2 in a specific tissue, the more will the number (0-5) in the confidence scale, and the darker will be green color of that organ in the figure, such as brain, liver, and spinal canal, small and large intestine shows high concentration of PSEN2. The tissue associations are acquired from curated information in UniProtKB manually. The confidence of individual association is implied by stars, where ????? is the most extraordinary confidence and ????? is the weakest
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| Conclusion | | |
The genes such as APP, PSEN1, and PSEN2 play an immensely crucial role in the onset of AD before 60 years of age. AD is a prominent neurodegenerative disorder. A lot of therapeutic interventions have come into sight to treat this disorder, but still, there is no cure for it; procedures implementing earlier analysis, such as cerebrospinal fluid biomarkers and amyloid positron-emission tomography neuroimaging are important to test this theory in clinical cases. We have characterized these three genes by using numerous databases such as GeneCards, Ensembl, UniPort, Swiss-model, human expression tissue, Human Protein Atlas More Details, and Human Gene Nomenclature Committee. We have merged the information regarding genomic location, subcellular localization, protein structures, details of protein structure, chemical properties, string interactants of a protein, amino acid sequence, and features of APP, PSEN1, and PSEN2 gene in my report. The purpose of genetic studies is important to know the cause of a particular disease and to check how an individual will react to a specific therapy, also the metabolism of the drug depends on the genetic framework in an individual, which is studied in detail in pharmacogenomics. Furthermore, studies of genes are important to provide gene therapy; according to a new research, gene therapy is provided to patients of AD to activate some of the genes that play a crucial role to protect neurons from getting degenerated.
Finally, we reach the conclusion that protein expression of APP is high in the brain, spinal canal, liver, lungs, and small and large intestine. PSEN1 concentration of expression is high in the brain and spinal, whereas PSEN2 concentration of expression is high in the liver, lungs, brain, and intestine. We also got to know the secondary structures of proteins such as APP, PSEN1, and PSEN2 are generally make right-handed alpha-helix and anti-parallel beta-sheets structure in the Ramachandran plot.
Patient informed consent
There is no need for patient informed consent.
Ethics committee approval
There is no need for ethics committee approval.
Financial support and sponsorship
No funding was received.
Conflicts of interest
There are no conflicts of interest to declare.
Author contribution subject and rate
- PunyaSachdeva (70%): Conducting analysis and literature review
- Faizan Ahmad (30%): Conducting literature review.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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