Structural Switch from Hairpin to Duplex/Antiparallel G-Quadruplex at Single-Nucleotide Polymorphism (SNP) Site of Human Apolipoprotein E (APOE) Gene Coding Region

Abstract

A gradual dementia, which leads to the loss of memory and intellectual abilities, is the main characteristics of Alzheimer’s disease. Amyloid-β (Aβ) plaques are the main components that accumulate and form clumps in the brains of people suffering from Alzheimer’s disease. Apolipoprotein E (APOE), an amyloid-binding protein is considered as one of the main genetic risk factor of the late-onset Alzheimer’s disease. Different isoforms of APOE gene named APOE2, APOE3, and APOE4 are known to exist, which differ from each other at certain positions involving single-nucleotide polymorphisms (SNPs). Out of these isoforms, APOE4 increases the risk of developing late-onset Alzheimer’s disease, whereas APOE3 is the most common among the general population. APOE4 differs from the common APOE3 by only one nucleotide at position +2985 (T to C), which results in immense alteration in the structure and function of the APOE gene. A combination of gel electrophoresis (polyacrylamide gel electrophoresis, PAGE), circular dichroism (CD), CD melting, thermal difference spectra and UV-thermal denaturation (TM) techniques was used to investigate the structural polymorphism associated with T → C single-nucleotide polymorphism (SNP) at the GC-rich sequence (d-TGGAGGACGTGTGCGGCCGCCT; APOE22T). Herein, we report that APOE22T DNA sequence switches between hairpin to antiparallel quadruplex from low to high oligomer concentration. On the contrary, its C-counterpart (APOE22C) forms hairpin as well as intermolecular antiparallel duplex structure. This structural change may possibly contribute to the protein recognition pattern, which, in turn, might control the APOE gene expression.

SNP rs10420324 in the AMPA receptor auxiliary subunit TARP γ-8 regulates the susceptibility to antisocial personality disorder

“…SNP rs10420324 is located in guanine-rich nucleic-acid sequences, which can form non-canonical structure G-quadruplexes 46 . Substantial evidence now exists to support that formation of DNA or RNA G-quadruplexes is coupled to altered gene expression by blocking the progression of RNA polymerase 46 – 48 . The variants of rs10420324 regulates the conformation and stability of the local G-quadruplex structure.…”

G-Quadruplexes in Neurobiology and Virology: Functional Roles and Potential Therapeutic Approaches

“… 58 Additionally, G4-related regulation of several other genes contributed to the pathogenetic ways for AD, including APP , 60 ADAM10 , 61 and APOE . 62 …”

“…Biochemical assays revealed that a G-rich sequence within exon 3 of BACE1 folds into a G4 structure, and this G4 prevented alternative splicing by hnRNP H. Following hnRNP H knockdown, a decrease in the level of the full-length BACE1 mRNA and a decrease in Aβ production were observed . Additionally, G4-related regulation of several other genes contributed to the pathogenetic ways for AD, including APP , ADAM10 , and APOE …”

“…58 Additionally, G4related regulation of several other genes contributed to the pathogenetic ways for AD, including APP, 60 ADAM10, 61 and APOE. 62 The Role of G4 in Regulating Noncoding RNAs Sortilin-related receptor 1 (SORL1) is responsible for the processing and trafficking of Aβ. The levels of mature microRNA-1229-3p (miR-1229-3p) have been shown to regulate SORL1 translation in neurons.…”

G‐quadruplex regulation of neural gene expression

“…The development of efficient isolation methods and highthroughput sequencing techniques [3,15,199,200] offers an opportunity to map the G-quadruplexes within the genome and transcriptome of specific classes of neurons and glia, as well as to determine how these maps changes during either development or disease. Moreover, combining these mapping efforts with SNP analysis will likely reveal classes of SNPs within the genome that impact nervous system gene expression and function by altering G-quadruplex formation and stability, as some studies have already suggested [113,186,201].…”