• Users Online: 57
  • Print this page
  • Email this page


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 8  |  Issue : 3  |  Page : 179-190

In silico characterization of predominant genes involved in early onset of alzheimer's disease


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 Submission15-Jul-2021
Date of Decision12-Nov-2021
Date of Acceptance19-Nov-2021
Date of Web Publication27-Dec-2021

Correspondence Address:
Punya Sachdeva
Amity Institute of Neuropsychology and Neurosciences, Amity University, Noida, Uttar Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jnbs.jnbs_34_21

Rights and Permissions
  Abstract 


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 28];8:179-90. Available from: http://www.jnbsjournal.com/text.asp?2021/8/3/179/333760




  Introduction Top


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

Click here to view
Table 1: The classification of Amyloid precursor protein, Presenilin- and Presenilin-2 genes

Click here to view



  Materials and Methods Top


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 Top


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 Top


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 2: The details of amyloid precursor protein 3-D protein structure

Click here to view
Table 3: The chemical properties of amyloid precursor protein of 770 amino acid residues

Click here to view


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

Click here to view


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

Click here to view
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

Click here to view


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)

Click here to view
Table 5: The chemical properties of Presenilin-1 of 467 amino acid residues

Click here to view


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

Click here to view
Table 7: The chemical properties of Presenilin-2 of 471 amino acid residues

Click here to view
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

Click here to view



  Conclusion Top


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.




 
  References Top

1.
Villain N, Dubois B. Alzheimer's disease including focal presentations. Semin Neurol 2019;39:213-26. doi: 10.1055/s-0039-1681041.  Back to cited text no. 1
    
2.
Mendez MF. Early-onset Alzheimer disease. Neurol Clin 2017;35:263-81. doi: 10.1016/j.ncl.2017.01.005.  Back to cited text no. 2
    
3.
Tellechea P, Pujol N, Esteve-Belloch P, Echeveste B, García-Eulate MR, Arbizu J, et al. Early- and late-onset Alzheimer disease: Are they the same entity? Enfermedad de Alzheimer de inicioprecoz y de iniciotardío: ¿son la mismaentidad?Neurologia (Barcelona, Spain) 2018;33:244-53. doi: 10.1016/j.nrl.2015.08.002.  Back to cited text no. 3
    
4.
Gallardo G, Holtzman DM. Amyloid-β and tau at the crossroads of Alzheimer's disease. Adv Exp Med Biol 2019;1184:187-203. doi: 10.1007/978-981-32-9358-8_16.  Back to cited text no. 4
    
5.
Penke B, Bogár F, Paragi G, Gera J, Fülöp L. Key peptides and proteins in Alzheimer's disease. Curr Protein Pept Sci 2019;20:577-99. doi: 10.2174/1389203720666190103123434.  Back to cited text no. 5
    
6.
Goedert M. NEURODEGENERATION. Alzheimer's and Parkinson's diseases: The prion concept in relation to assembled Aβ, tau, and α-synuclein. Science (New York, N.Y.) 2015;349:1255555. doi: 10.1126/science.1255555.  Back to cited text no. 6
    
7.
Armstrong RA. Risk factors for Alzheimer's disease. Folia Neuropathol 2019;57:87-105. doi: 10.5114/fn.2019.85929.  Back to cited text no. 7
    
8.
Lyu J, Zhang J, Mu H, Li W, Champ M, Xiong Q, et al. The effects of music therapy on cognition, psychiatric symptoms, and activities of daily living in patients with Alzheimer's disease. J Alzheimers Dis 2018;64:1347-58. doi: 10.3233/JAD-180183.  Back to cited text no. 8
    
9.
Cummings JL, Tong G, Ballard C. Treatment combinations for Alzheimer's disease: Current and future pharmacotherapy options. J Alzheimers Dis 2019;67:779-94. doi: 10.3233/JAD-180766.  Back to cited text no. 9
    
10.
Fessel J. Alzheimer's disease combination treatment. Neurobiol Aging 2018;63:165. doi: 10.1016/j.neurobiolaging. 2017.10.022.  Back to cited text no. 10
    
11.
Wang J, Yu JT, Wang HF, Meng XF, Wang C, Tan CC, et al. Pharmacological treatment of neuropsychiatric symptoms in Alzheimer's disease: A systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2015;86:101-9. doi: 10.1136/jnnp-2014-308112.  Back to cited text no. 11
    
12.
Zaritsky R. To alois alzheimer, from auguste deter. Ann Intern Med 2021;174:843. doi: 10.7326/M20-3816.  Back to cited text no. 12
    
13.
Pantel J. Alzheimer's disease from Auguste Deter to the present: Progress, disappointments and open questions. Z Gerontol Geriatr 2017;50:576-87. doi: 10.1007/s00391-017-1307-2.  Back to cited text no. 13
    
14.
Cipriani G, Dolciotti C, Picchi L, Bonuccelli U. Alzheimer and his disease: A brief history. Neurol Sci 2011;32:275-9. doi: 10.1007/s10072-010-0454-7.  Back to cited text no. 14
    
15.
Lazarczyk MJ, Hof PR, Bouras C, Giannakopoulos P. Preclinical Alzheimer disease: Identification of cases at risk among cognitively intact older individuals. BMC Med 2012;10:127. doi: 10.1186/1741-7015-10-127.  Back to cited text no. 15
    
16.
Duyckaerts C, Brion JP, Hauw JJ, Flament-Durand J. Quantitative assessment of the density of neurofibrillary tangles and senile plaques in senile dementia of the Alzheimer type. Comparison of immunocytochemistry with a specific antibody and Bodian'sprotargol method. Acta Neuropathol1987;73:167-70. doi: 10.1007/BF00693783.  Back to cited text no. 16
    
17.
Huynh TV, Holtzman DM. In search of an identity for amyloid plaques. Trends Neurosci 2018;41:483-6. doi: 10.1016/j.tins.2018.06.002.  Back to cited text no. 17
    
18.
Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer's disease: Their nature and pathogenesis. Appl Pathol 1984;2:357-69.  Back to cited text no. 18
    
19.
Ikeda S. Yakubutsu, seishin, kodo. Jpn J Psychopharmacol 1992;12:141-9.  Back to cited text no. 19
    
20.
Youn K, Lee J, Yun EY. Biological evaluation and in silico docking study of γ-linolenic acid as a potential BACE1 inhibitor. J Funct Foods 2014;10:187-91. doi: 10.1016/j.jff.2014.06.005.  Back to cited text no. 20
    
21.
Dhananjayan K, Arunachalam S, Raj BA. Targeting BACE 1(Beta secretase) through Polyphenolic compounds – A computational in silico approach with emphasis on binding site analysis. J Comput Methods Mol Design 2014;4:14-24.  Back to cited text no. 21
    
22.
Khan N, Khanna K, Gangwar P, Mohan A, Kumar S. Insilico approach to predict the structure of amyloid precursor protein responsible for Alzheimer's disease. J Adv Bioinform Appl Res 2012;3:333-8.  Back to cited text no. 22
    
23.
Robinson M, Lee BY, Hane FT. Recent progress in Alzheimer's disease research, part 2: Genetics and epidemiology. J Alzheimers Dis 2017;57:317-30. doi: 10.3233/JAD-161149.  Back to cited text no. 23
    
24.
Zhu JB, Tan CC, Tan L, Yu JT. State of play in Alzheimer's disease genetics. J Alzheimers Dis 2017;58:631-59. doi: 10.3233/JAD-170062.  Back to cited text no. 24
    
25.
Esquerda-Canals G, Montoliu-Gaya L, Güell-Bosch J, Villegas S. Mouse models of Alzheimer's disease. J Alzheimers Dis 2017;57:1171-83. doi: 10.3233/JAD-170045.  Back to cited text no. 25
    
26.
Jørgensen AL, Johannsen P. Alzheimer's disease and genes. Ugeskr Laeger 1997;159:5648-52.  Back to cited text no. 26
    
27.
El Gaamouch F, Jing P, Xia J, Cai D. Alzheimer's disease risk genes and lipid regulators. J Alzheimers Dis 2016;53:15-29. doi: 10.3233/JAD-160169.  Back to cited text no. 27
    
28.
Vasquez JB, Simpson JF, Harpole R, Estus S. Alzheimer's disease genetics and ABCA7 splicing. J Alzheimers Dis 2017;59:633-41. doi: 10.3233/JAD-170872.  Back to cited text no. 28
    
29.
Cacace R, Sleegers K, Van Broeckhoven C. Molecular genetics of early-onset Alzheimer's disease revisited. Alzheimers Dement 2016;12:733-48. doi: 10.1016/j.jalz.2016.01.012.  Back to cited text no. 29
    
30.
Giau VV, Bagyinszky E, Youn YC, An SS, Kim S. APP, PSEN1, and PSEN2 mutations in Asian patients with early-onset Alzheimer disease. Int J Mol Sci 2019;20:4757. doi: 10.3390/ijms20194757.  Back to cited text no. 30
    
31.
Piaceri I, Nacmias B, Sorbi S. Genetics of familial and sporadic Alzheimer's disease. Front Biosci (Elite edition) 2013;5:167-77. doi:10.2741/e605.  Back to cited text no. 31
    
32.
Giri M, Zhang M, Lü Y. Genes associated with Alzheimer's disease: An overview and current status. Clin Interv Aging 2016;11:665-81. doi: 10.2147/CIA.S105769.  Back to cited text no. 32
    
33.
Wisniewski KE, Dalton AJ, McLachlan C, Wen GY, Wisniewski HM. Alzheimer's disease in Down's syndrome: Clinicopathologic studies. Neurology 1985;35:957-61. doi: 10.1212/wnl.35.7.957.  Back to cited text no. 33
    
34.
Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: Sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun 1984;122:1131-5. doi: 10.1016/0006-291x(84)91209-9.  Back to cited text no. 34
    
35.
Glenner GG, Wong CW. Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984;120:885-90. doi: 10.1016/s0006-291x(84)80190-4.  Back to cited text no. 35
    
36.
Cruts M, Theuns J, Van Broeckhoven C. Locus-specific mutation databases for neurodegenerative brain diseases. Hum Mutat 2012;33:1340-4. doi: 10.1002/humu.22117.  Back to cited text no. 36
    
37.
Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991;12:383-8. doi: 10.1016/0165-6147(91)90609-v.  Back to cited text no. 37
    
38.
Lok K, Zhao H, Shen H, Wang Z, Gao X, Zhao W, et al. Characterization of the APP/PS1 mouse model of Alzheimer's disease in senescence accelerated background. Neurosci Lett 2013;557:84-9. doi: 10.1016/j.neulet.2013.10.051.  Back to cited text no. 38
    
39.
Lanoiselée HM, Nicolas G, Wallon D, Rovelet-Lecrux A, Lacour M, Rousseau S, et al. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases. PLoS Med 2017;14:e1002270. doi: 10.1371/journal.pmed.1002270.  Back to cited text no. 39
    
40.
Li L, Kim HJ, Roh JH, Kim M, Koh W, Kim Y, et al. Pathological manifestation of the induced pluripotent stem cell-derived cortical neurons from an early-onset Alzheimer's disease patient carrying a presenilin-1 mutation (S170F). Cell Prolif 2020;53:e12798. doi: 10.1111/cpr.12798.  Back to cited text no. 40
    
41.
Aathi M, Piramanayagam S. From EST to structure models for functional inference of APP, BACE1, PSEN1, PSEN2 genes. Bioinformation 2019;15:760-71. doi: 10.6026/97320630015760.  Back to cited text no. 41
    
42.
Hsu S, Pimenova AA, Hayes K, Villa JA, Rosene MJ, Jere M, et al. Systematic validation of variants of unknown significance in APP, PSEN1 and PSEN2. Neurobiol Dis 2020;139:104817. doi: 10.1016/j.nbd.2020.104817.  Back to cited text no. 42
    


    Figures

  [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]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Materials and Me...
Results
Discussion
Conclusion
References
Article Figures
Article Tables

 Article Access Statistics
    Viewed1745    
    Printed36    
    Emailed0    
    PDF Downloaded227    
    Comments [Add]    

Recommend this journal


[TAG2]
[TAG3]
[TAG4]