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10 pages, 21856 KiB

Open AccessCommunication

A Possible Pathogenic PSEN2 Gly56Ser Mutation in a Korean Patient with Early-Onset Alzheimer’s Disease

by Kyu-Hwan Shim, Min-Ju Kang, Heewon Bae, Danyeong Kim, Jiwon Park, Seong-Soo A. An and Da-Eun Jeong

Int. J. Mol. Sci. 2022, 23(6), 2967; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23062967 - 09 Mar 2022

Cited by 2 | Viewed by 2069

Abstract

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), [...] Read more.

Early-onset Alzheimer’s disease (EOAD) is characterized by the presence of neurological symptoms in patients with Alzheimer’s disease (AD) before 65 years of age. Mutations in pathological genes, including amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2), were associated with EOAD. Seventy-six mutations in PSEN2 have been found around the world, which could affect the activity of γ-secretase in amyloid beta processing. Here, a heterozygous PSEN2 point mutation from G to A nucleotide change at position 166 (codon 56; c.166G>A, Gly56Ser) was identified in a 64-year-old Korean female with AD with progressive cognitive memory impairment for the 4 years prior to the hospital visit. Hippocampal atrophy was observed from magnetic resonance imaging-based neuroimaging analyses. Temporal and parietal cortex hypometabolisms were identified using fluorodeoxyglucose positron emission tomography. This mutation was at the N-terminal portion of the presenilin 2 protein on the cytosolic side. Therefore, the serine substitution may have promoted AD pathogenesis by perturbing to the mutation region through altered phosphorylation of presenilin. In silico analysis revealed that the mutation altered protein bulkiness with increased hydrophilicity and reduced flexibility of the mutated region of the protein. Structural changes were likely caused by intramolecular interactions between serine and other residues, which may have affected APP processing. The functional study will clarify the pathogenicity of the mutation in the future. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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12 pages, 1454 KiB

Open AccessArticle

Alternative Splicing Regulation of Low-Frequency Genetic Variants in Exon 2 of TREM2 in Alzheimer’s Disease by Splicing-Based Aggregation

by Seonggyun Han, Yirang Na, Insong Koh, Kwangsik Nho and Younghee Lee

Int. J. Mol. Sci. 2021, 22(18), 9865; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22189865 - 13 Sep 2021

Cited by 9 | Viewed by 2439

Abstract

TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in [...] Read more.

TREM2 is among the most well-known Alzheimer’s disease (AD) risk genes; however, the functional roles of its AD-associated variants remain to be elucidated, and most known risk alleles are low-frequency variants whose investigation is challenging. Here, we utilized a splicing-guided aggregation method in which multiple low-frequency TREM2 variants were bundled together to investigate the functional impact of those variants on alternative splicing in AD. We analyzed whole genome sequencing (WGS) and RNA-seq data generated from cognitively normal elderly controls (CN) and AD patients in two independent cohorts, representing three regions in the frontal lobe of the human brain: the dorsolateral prefrontal cortex (CN = 213 and AD = 376), frontal pole (CN = 72 and AD = 175), and inferior frontal (CN = 63 and AD = 157). We observed an exon skipping event in the second exon of TREM2, with that exon tending to be more frequently skipped (p = 0.0012) in individuals having at least one low-frequency variant that caused loss-of-function for a splicing regulatory element. In addition, genes differentially expressed between AD patients with high vs. low skipping of the second exon (i.e., loss of a TREM2 functional domain) were significantly enriched in immune-related pathways. Our splicing-guided aggregation method thus provides new insight into the regulation of alternative splicing of the second exon of TREM2 by low-frequency variants and could be a useful tool for further exploring the potential molecular mechanisms of multiple, disease-associated, low-frequency variants. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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8 pages, 1259 KiB

Open AccessCommunication

Alternative Splicing Regulation of an Alzheimer’s Risk Variant in CLU

by Seonggyun Han, Kwangsik Nho and Younghee Lee

Int. J. Mol. Sci. 2020, 21(19), 7079; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21197079 - 25 Sep 2020

Cited by 9 | Viewed by 2799

Abstract

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been [...] Read more.

Clusterin (CLU) is one of the risk genes most associated with late onset Alzheimer’s disease (AD), and several genetic variants in CLU are associated with AD risk. However, the functional role of known AD risk genetic variants in CLU has been little explored. We investigated the effect of an AD risk variant (rs7982) in the 5th exon of CLU on alternative splicing by using an integrative approach of brain-tissue-based RNA-Seq and whole genome sequencing data from Accelerating Medicines Partnership—Alzheimer’s Disease (AMP-AD). RNA-Seq data were generated from three regions in the temporal lobe of the brain—the temporal cortex, superior temporal gyrus, and parahippocampal gyrus. The rs7982 was significantly associated with intron retention (IR) of the 5th exon of CLU; as the number of alternative alleles (G) increased, the IR rates decreased more significantly in females than in males. Our results suggest a sex-dependent role of rs7982 in AD pathogenesis via splicing regulation. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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19 pages, 1111 KiB

Open AccessArticle

Quantitative Trait Module-Based Genetic Analysis of Alzheimer’s Disease

by Shaoxun Yuan, Haitao Li, Jianming Xie and Xiao Sun

Int. J. Mol. Sci. 2019, 20(23), 5912; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20235912 - 25 Nov 2019

Cited by 6 | Viewed by 3247

Abstract

The pathological features of Alzheimer’s Disease (AD) first appear in the medial temporal lobe and then in other brain structures with the development of the disease. In this work, we investigated the association between genetic loci and subcortical structure volumes of AD on [...] Read more.

The pathological features of Alzheimer’s Disease (AD) first appear in the medial temporal lobe and then in other brain structures with the development of the disease. In this work, we investigated the association between genetic loci and subcortical structure volumes of AD on 393 samples in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Brain subcortical structures were clustered into modules using Pearson’s correlation coefficient of volumes across all samples. Module volumes were used as quantitative traits to identify not only the main effect loci but also the interactive effect loci for each module. Thirty-five subcortical structures were clustered into five modules, each corresponding to a particular brain structure/area, including the limbic system (module I), the corpus callosum (module II), thalamus–cerebellum–brainstem–pallidum (module III), the basal ganglia neostriatum (module IV), and the ventricular system (module V). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicate that the gene annotations of the five modules were distinct, with few overlaps between different modules. We identified several main effect loci and interactive effect loci for each module. All these loci are related to the function of module structures and basic biological processes such as material transport and signal transduction. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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23 pages, 2659 KiB

Open AccessArticle

APP, PSEN1, and PSEN2 Mutations in Asian Patients with Early-Onset Alzheimer Disease

by Vo Van Giau, Eva Bagyinszky, Young Chul Youn, Seong Soo A. An and SangYun Kim

Int. J. Mol. Sci. 2019, 20(19), 4757; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms20194757 - 25 Sep 2019

Cited by 39 | Viewed by 6705

Abstract

The number of patients with Alzheimer’s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these [...] Read more.

The number of patients with Alzheimer’s disease (AD) is rapidly increasing in Asia. Mutations in the amyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) genes can cause autosomal dominant forms of early-onset AD (EOAD). Although these genes have been extensively studied, variant classification remains a challenge, highlighting the need to colligate mutations across populations. In this study, we performed a genetic screening for mutations in the APP, PSEN1, and PSEN2 genes in 200 clinically diagnosed EOAD patients across four Asian countries, including Thailand, Malaysia, the Philippines, and Korea, between 2009 and 2018. Thirty-two (16%) patients presented pathogenic APP, PSEN1, or PSEN2 variants; eight (25%), 19 (59%), and five (16%) of the 32 patients presented APP, PSEN1, and PSEN2 variants, respectively. Among the 21 novel and known non-synonymous variants, five APP variants were found in Korean patients and one APP variant was identified in a Thai patient with EOAD. Nine, two, and one PSEN1 mutation was found in a Korean patient, Malaysian siblings, and a Thai patient, respectively. Unlike PSEN1 mutations, PSEN2 mutations were rare in patients with EOAD; only three variants were found in Korean patients with EOAD. Comparison of AD-causative point mutations in Asian countries; our findings explained only a small fraction of patients, leaving approximately 84% (p = 0.01) of autosomal dominant pedigrees genetically unexplained. We suggest that the use of high-throughput sequencing technologies for EOAD patients can potentially improve our understanding of the molecular mechanisms of AD. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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Review

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20 pages, 2270 KiB

Open AccessReview

Transcriptomics in Alzheimer’s Disease: Aspects and Challenges

by Eva Bagyinszky, Vo Van Giau and SeongSoo A. An

Int. J. Mol. Sci. 2020, 21(10), 3517; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21103517 - 15 May 2020

Cited by 34 | Viewed by 7299

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia. Although the heritability of AD is high, the knowledge of the disease-associated genes, their expression, and their disease-related pathways remain limited. Hence, finding the association between gene dysfunctions and pathological mechanisms, such as [...] Read more.

Alzheimer’s disease (AD) is the most common cause of dementia. Although the heritability of AD is high, the knowledge of the disease-associated genes, their expression, and their disease-related pathways remain limited. Hence, finding the association between gene dysfunctions and pathological mechanisms, such as neuronal transports, APP processing, calcium homeostasis, and impairment in mitochondria, should be crucial. Emerging studies have revealed that changes in gene expression and gene regulation may have a strong impact on neurodegeneration. The mRNA–transcription factor interactions, non-coding RNAs, alternative splicing, or copy number variants could also play a role in disease onset. These facts suggest that understanding the impact of transcriptomes in AD may improve the disease diagnosis and also the therapies. In this review, we highlight recent transcriptome investigations in multifactorial AD, with emphasis on the insights emerging at their interface. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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18 pages, 1600 KiB

Open AccessReview

The Genetics of Alzheimer’s Disease in the Chinese Population

by Chen-Ling Gan, Tao Zhang and Tae Ho Lee

Int. J. Mol. Sci. 2020, 21(7), 2381; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21072381 - 30 Mar 2020

Cited by 9 | Viewed by 4690

Abstract

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. In recent years, through the advancement of genome-wide association [...] Read more.

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. In recent years, through the advancement of genome-wide association studies, second-generation gene sequencing technology, and their application in AD genetic research, more genetic loci associated with the risk for AD have been discovered, including KCNJ15, TREM2, and GCH1, which provides new ideas for the etiology and treatment of AD. This review summarizes three early-onset AD causative genes (APP, PSEN1, and PSEN2) and some late-onset AD susceptibility genes and their mutation sites newly discovered in China, and briefly introduces the potential mechanisms of these genetic susceptibilities in the pathogenesis of AD, which would help in understanding the genetic mechanisms underlying this devastating disease. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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18 pages, 626 KiB

Open AccessReview

Undiscovered Roles for Transthyretin: From a Transporter Protein to a New Therapeutic Target for Alzheimer’s Disease

by Tiago Gião, Joana Saavedra, Ellen Cotrina, Jordi Quintana, Jordi Llop, Gemma Arsequell and Isabel Cardoso

Int. J. Mol. Sci. 2020, 21(6), 2075; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms21062075 - 18 Mar 2020

Cited by 40 | Viewed by 5974

Abstract

Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding [...] Read more.

Transthyretin (TTR), an homotetrameric protein mainly synthesized by the liver and the choroid plexus, and secreted into the blood and the cerebrospinal fluid, respectively, has been specially acknowledged for its functions as a transporter protein of thyroxine and retinol (the latter through binding to the retinol-binding protein), in these fluids. Still, this protein has managed to stay in the spotlight as it has been assigned new and varied functions. In this review, we cover knowledge on novel TTR functions and the cellular pathways involved, spanning from neuroprotection to vascular events, while emphasizing its involvement in Alzheimer’s disease (AD). We describe details of TTR as an amyloid binding protein and discuss its interaction with the amyloid Aβ peptides, and the proposed mechanisms underlying TTR neuroprotection in AD. We also present the importance of translating advances in the knowledge of the TTR neuroprotective role into drug discovery strategies focused on TTR as a new target in AD therapeutics. Full article

(This article belongs to the Special Issue Molecular Genetic of Alzheimer's Disease)

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