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Advanced Neurology Genomic insights into Alzheimer

This phenotypic heterogeneity may also be influenced by of correlations between protein physicochemical properties
the mutation type, as observed in the Osaka mutation and clinical phenotype is illustrated in Figure 1.
(E693Del), which primarily presents as a neurological
disease with progressive cognitive decline and focal 2.2. Analysis of the physicochemical properties of
neurological symptoms, such as loss of movement and wild-type and mutated human amyloid precursor
spastic quadriplegia [17,18] . These clinical symptoms are not proteins
commonly observed in patients with mutations occurring Initially, the FASTA-formatted human APP sequence
at this residue location. (P05067) was obtained from the UniProtKB/SwissProt
[20]
Identifying the genes and subsequent mutations (www.uniprot.org/uniprotkb) database . Subsequently,
responsible for fAD is crucial for advancing our APP sequences were copied and altered to represent all
understanding of AD’s underlying mechanisms. This mutations (21 APP mutations) categorized as pathogenic
knowledge not only informs future disease treatment but for AD according to the AlzForum (www.alzforum.org)
also fosters interest in the application of genetic testing and APP mutation database at the time of access in 2020.
counseling in clinical practice . Despite this importance, AlzForum serves as a new platform and information
[19]
limited investigation has been conducted concerning the database regularly updated to include the most up-to-date
diverse effects of different mutations within the same research findings, fostering discovery and advancements
[21]
gene that encodes a single protein on the clinical features in treatment .
and progression of fAD subtypes. The multitude of To analyze the physicochemical properties of both the
mutation subtypes within the APP gene provides a unique wild-type and each mutated human APP sequence, the
opportunity to explore this connection. ExPASy ProtParam tool (web.expasy.org/protparam/) was
Herein, we undertook a comprehensive comparison of employed. This tool facilitates the calculation of various
the clinical and neuropathological severity observed in fAD physical and chemical parameters based on the provided
ethno-genetic subtypes. Our study involved an extensive FASTA format, including molecular weight (MW),
analysis aimed at investigating whether the specific location theoretical isoelectric point (pI), extinction coefficient
of mutations on the APP gene and the physicochemical (EC), instability index (II), aliphatic index (AI), and grand
[22]
properties of the encoded protein contribute to variations average of hydropathicity (GRAVY) .
in clinical and neuropathological presentations within 2.3. Prediction and refinement of three-dimensional
these subtypes. This analysis considers clinical severity, (3D) structures of the wild-type and mutated human
pathogenicity, neuropathology, biological processes, APP sequences
and the relationship between the properties of each
APP mutation and the severity of the disease. Strikingly, Protein 3D structures for both the wild-type and mutated
our findings reveal the most significant disparities in human APP sequences were generated using each FASTA-
mutations occurring between amino acids 714 – 723 on the formatted sequence through the I-TASSER (Iterative
C-terminal region of the APP gene compared to mutations Threading Assembly Refinement) Server (seq2fun.dcmb.
occurring toward the N-terminal region. Mutations med.umich.edu//I-TASSER/). I-TASSER, a protein 3D
within the 714 – 717 region exhibit the greatest diversity structure prediction server, operates by predicting protein
of symptoms, including seizures and/or myoclonus, and structures from linear sequences. This process involves
are associated with an earlier average disease onset, the initial identification of structural templates from the
coupled with a slightly higher APP instability index. These Protein Data Bank (PDB), followed by the construction
results underscore the important role of disease-specific of full-length protein models through iterative template-
[23-25]
mutations within the APP gene in shaping the clinical based fragment assembly simulations . Subsequent to
and neuropathological outcomes, as well as the onset and structure prediction, each model was refined using the
severity of AD. Consequently, our study underscores the Galaxy Web’s GalaxyRefine server (galaxy.seoklab.org).
need for an ethno-genetic assessment when formulating This server enhances structural quality through repeated
diagnostic and therapeutic strategies. structural disturbances and subsequent relaxations
facilitated by molecular dynamics simulations, ultimately
2. Materials and methods improving the overall quality of the protein structures [26,27] .
2.1. Materials 2.4. Evaluation of the quality of the predicted initial
The flow chart depicting the overall materials and and refined protein models
methods for sequence retrieval from the protein database, The quality assessment of both initial and refined protein
bioinformatics analysis of the sequences, and identification models involved the utilization of various tools, including

Volume 2 Issue 4 (2023) 3 https://doi.org/10.36922/an.1734