Novel amyloid precursor protein mutation, Val669Leu (“Seoul <i>APP</i>”), in a Korean patient with early-onset Alzheimer's disease

Bagyinszky, Eva,Kang, Min Ju,Van Giau, Vo,Shim, KyuHwan,Pyun, Jung-Min,Suh, Jeewon,An, Seong Soo A.,Kim, SangYun Elsevier 2019 NEUROBIOLOGY OF AGING Vol.84 No.-

<P><B>Abstract</B></P> <P>In this study, a novel mutation in <I>APP</I> gene, Val669Leu (“Seoul <I>APP</I>”), was reported in a Korean female patient with Alzheimer's disease. She developed cognitive decline at 56 years of age, and her memory declined rapidly over one-year period from her 1st visit to the hospital. Her Mini-Mental State Examination scores dropped from 25/30 to 13/30. Two years later, she developed parkinsonian features, myoclonic jerk, and generalized seizure. As the disease progressed, aggravated diffuse brain atrophy and small-vessel ischemic lesion was also observed, and she became mute and vegetative in 4 years from the symptom onset. Magnetic resonance imaging showed mild medial temporal lobe and hippocampal atrophy, and 18F-fluoro-deoxyglucose positron emission tomography showed bilateral temporoparietal hypometabolism. Plasma amyloid oligomer analysis revealed highly elevated Aβ oligomers levels in the proband patient. Family history revealed positive without biochemical confirmation because family members testified similar type of cognitive decline from the proband's mother and one of her aunt/uncle. Her half-siblings did not present any signs of memory impairment. Sanger sequencing of the proband patient revealed a novel mutation in <I>APP</I> gene, Val669Leu, but mutation was not found in her unaffected half-sisters. A designed algorithm by Guerreiro et al. on early-onset Alzheimer's disease–associated mutations suggested the mutation as possibly pathogenic mutation. On the other hand, PolyPhen2 and SIFT tools suggested as otherwise. Since the mutation was located nearby the β-secretase cleavage site of APP, right next to the Swedish APP (Lys,Met670/671Asn,Leu) mutation, it was named as “Seoul <I>APP”</I> mutation. 3D modeling revealed that this mutation could result in significant changes in loop orientation of APP and also its intramolecular interactions. Hence, a novel <I>APP</I> Val669Leu mutation could alter the binding interactions between APP and β-secretase, which may influence the Aβ40 and Aβ42 generations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A novel variant in APP, Val669Leu, was found in a Korean patient, named Seoul APP. </LI> <LI> Proband patient developed disease phenotype in her 50s. </LI> <LI> Family history may be positive, and mutation may segregate with disease. </LI> <LI> Mutation is located nearby the beta-secretase site of APP, and potentially disturbs the enzyme mechanism. </LI> </UL> </P>

In silico modeling of pathogenic point mutations in PSEN1 as studied in South-east Asia

Bagyinszky, E.,Bae, S.,Kim, S.,An, S. S. Springer Science + Business Media 2016 Toxicology and Environmental Health Sciences Vol.8 No.2

<i>PSEN1</i> p.Thr116Ile Variant in Two Korean Families with Young Onset Alzheimer’s Disease

Bagyinszky, Eva,Lee, Hye-Mi,Van Giau, Vo,Koh, Seong-Beom,Jeong, Jee Hyang,An, Seong Soo A.,Kim, SangYun MDPI 2018 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.19 No.9

<P>An in depth study of <I>PSEN1</I> mutation p.Thr116Ile (c.335C>T) is presented from two Korean families with autosomal dominant inheritance. Clinical manifestation of our patients included memory loss, attention deficits, visuospatial dysfunction, agnosia, aphasia, apraxia, and personality changes, which occurred in their 30s. <I>PSEN1</I> Thr116Ile was initially discovered in an Italian patient and two French families with early onset Alzheimer’s disease (EOAD) with similar age of onset. To verify the possible pathogenic mechanisms of mutation, <I>in silico</I> predictions and 3D modeling were performed. Structure predictions revealed significant aberrations in first hydrophilic loop (HL-I loop). The hydrophobic isoleucine could alter the loop orientation through increased hydrophobic contacts with the surrounding amino acids. Mutation could destroy a possible hydrogen bond between tyrosine 115 and threonine 116, which may affect the loop conformation. HL-I was confirmed as a conservative region of <I>PSEN1</I>, which may be critical in <I>PSEN1</I> functions. An additional pathogenic mutation, <I>PSEN1</I> Thr116Asn, was also found for the same residue, where the patient presented young onset AD (YOND). Other mutations in HL-I loop, such as Tyr115His and Glu120Asp, were described in patients with YOND, supporting the critical role of HL-I loop in <I>PSEN1</I> activity.</P>

Characterization of Inflammatory Biomarkers and Candidates for Diagnosis of Alzheimer’s Disease

Bagyinszky Eva,안성수,Young-Chul Youn,김상윤 한국바이오칩학회 2014 BioChip Journal Vol.8 No.3

Alzheimer’s disease (AD) is the most common form of neurodegenerative dementia, several genetic, non-genetic, and environmental factors could be involved in disease progression. Association was suggested between inflammation and AD progression. Since neuroinflammation can be involved in neurodegeneration, studies suggested that several inflammatory molecules (cytokines) might enhance the inflammation or suppress the immune system. Altered cytokine levels might reflect the neuropathological changes in patients. This review summarizes the validated and potential inflammatory biomarkers in AD, and it is focusing on interleukins (ILs), interferons (IFNs) and tumor necrosis factors (TNFs). Interleukins have dual role in the AD progression: Several ILs(such as IL1, IL6 or IL8) can promote the disease-associated inflammatory pathways, while the others (such as IL1ra, IL4 or IL10) might be involved in the neuroprotectionand dementia prevention. Conflicting reports are available on the role of IFNs (IFNα, IFNβ and IFNγ) in AD progression. Several studies reported that they might have neuroprotective effects, but the others suggested that they can contribute to neurotoxiciy by inducing the pro-inflammatory cytokines. TNFα can be expressed with other pro-inflammatory cytokines and induce the neurodegeneration. Both TNFα and TNFR were suggested as successful markers for AD and dementia. Several cytokines can be used to distinguish the AD patients from the healthy individuals, since their expression might be up-or down-regulated in the brain of AD patients. Some cytokines might be useful to measure the severity of the disorder. Overproduction of pro-inflammatory molecules could result neuroinflammation and enhance the neurotoxicity. Inhibiting the pro-inflammatory- and/ or inducing the anti-inflammatory molecules might improve the therapies or AD.

Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis

Bagyinszky, Eva,Giau, Vo Van,Shim, Kyuhwan,Suk, Kyoungho,An, Seong Soo A.,Kim, SangYun Elsevier Pub. Co 2017 Journal of the neurological sciences Vol.376 No.-

<P><B>Abstract</B></P> <P>Alzheimer's disease (AD) is a complex disorder and the most common form of neurodegenerative dementia. Several genetic, environmental, and physiological factors, including inflammations and metabolic influences, are involved in the progression of AD. Inflammations are composed of complicated networks of many chemokines and cytokines with diverse cells. Inflammatory molecules are needed for the protection against pathogens, and maintaining their balances is important for normal physiological function. Recent studies demonstrated that inflammation may be involved in neurodegenerative dementia. Cellular immune components, such as microglia or astrocytes, mediate the release of inflammatory molecules, including tumor necrosis factor, growth factors, adhesion molecules, or chemokines. Over- and underexpression of pro- and anti-inflammatory molecules, respectively, may result in neuroinflammation and thus disease initiation and progression. In addition, levels of several inflammatory factors were reported to be altered in the brain or bodily fluids of patients with AD, reflecting their neuropathological changes. Therefore, simultaneous detection of several inflammatory molecules in the early or pre-symptomatic stage may improve the early diagnosis of AD. Further studies are needed to determine, how induction or inhibition of inflammatory factors could be used for AD therapies. This review summarizes the role or possible role of immune cells and inflammatory molecules in disease progression or prevention.</P> <P><B>Highlights</B></P> <P> <UL> <LI> In this review we introduce how inflammation could be involved in Alzheimer’s disease (AD) </LI> <LI> We introduce the role of the cellular components of inflammation </LI> <LI> We summarize the inflammatory molecules and their roles in neurodegeneration and AD progression </LI> <LI> Inflammatory molecules can be successful biomarkers, used in the diagnosis and prevention of AD. </LI> </UL> </P>

In silico modeling of pathogenic or possibly pathogenic point mutations in PSEN2

Yan Cai,Eva Bagyinszky,안성수,김상윤,Eva Bagyinszky 대한독성 유전단백체 학회 2016 Molecular & cellular toxicology Vol.12 No.4

Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder that affects memory, thinking, and behavior. 3 genes found to be involved in early-onset AD encode amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2). Presenilin mutations play a key role, with more than 200 mutations described for PSEN1 and approximately 40 for PSEN2. However, whether mutations cause disease or have effects on protein function is often unknown. For further study, such as genetic counseling and pathogenesis, the important thing we need do is to classify mutations into “pathogenic” or “not pathogenic”. Building a structural context in cell for all mutations is expensive and time consuming. In this study, we summarized substitution mutations in the PSEN2 gene and attempted to identify pathogenic mutations using Polyphen2 (polymorphism phenotyping v2), SIFT (Sorting Intolerant From Tolerant), and 3-D structure analysis techniques.

In silico modeling of pathogenic or possibly pathogenic point mutations in PSEN2

Cai, Yan,Bagyinszky, Eva,An, Seong Soo A.,Kim, SangYun THE KOREAN SOCIETY OF TOXICOGENOMICS AND TOXICOPRP 2016 MOLECULAR AND CELLULAR TOXICOLOGY Vol. No.

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder that affects memory, thinking, and behavior. 3 genes found to be involved in early-onset AD encode amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2). Presenilin mutations play a key role, with more than 200 mutations described for PSEN1 and approximately 40 for PSEN2. However, whether mutations cause disease or have effects on protein function is often unknown. For further study, such as genetic counseling and pathogenesis, the important thing we need do is to classify mutations into 'pathogenic' or 'not pathogenic'. Building a structural context in cell for all mutations is expensive and time consuming. In this study, we summarized substitution mutations in the PSEN2 gene and attempted to identify pathogenic mutations using Polyphen2 (polymorphism phenotyping v2), SIFT (Sorting Intolerant From Tolerant), and 3-D structure analysis techniques.

Additional diagnostic testing of the 2019 novel coronavirus (SARS-CoV-2)

Van Giau Vo,Eva Bagyinszky,심규환,Park Yoon Soo,An Seong Soo A. 대한독성 유전단백체 학회 2020 Molecular & cellular toxicology Vol.16 No.4

Purpose of review Within the last two decades several members of the Coronaviridae family namely Severe Respiratory Syndrome (SARS-CoV) and Middle East Respiratory Syndrome (MERS-CoV) have demonstrated epidemic potential. In late, 2019 an unnamed genetic relative, later named SARS-CoV-2 realized its potential in the highly populous neighborhoods of Wuhan, China. Unchecked, the virus rapidly spread among interconnected communities and related households before containment measures could be in acted. “Appropriate” diagnostic testing in response to the SARS-CoV-2 outbreak should be urgently considered. This perspective review gives particular attention to the potential diagnostic testing of the virus in semen and seminal fuids due to its high levels of angiotensin converting enzyme 2 (ACE2) precursor. Recent fndings As many infectious viruses are stable in semen and have transmitted the respective diseases, the presence of SARS-CoV-2 should be tested in semen to assess their stabilities and half-life. As in case of Ebola virus, it was present in semen for longer period in a carrier man without any symptom. Additional hypothesis is that since ACE2 could serve as a mediator for the endocytosis of the previously SARS coronavirus, SARS-CoV-2 may enter the cells through similar mechanism. From the protein expression atlas, high levels of ACE2 precursor were found in intestines and testis. Hence, the testis and seminal fuids could be the host cell and/or reservoir. The results could be used as a suggestive guideline for the sexual activities after the discharge or declaration of disease free.

Clinical genetic strategies for early onset neurodegenerative diseases

Vo Van Giau,Eva Bagyinszky,안성수,SangYun Kim 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.2

Purpose of review: Methods for the genetic diagnosis of neurodegenerative disorders were reviewed, including their backgrounds and applications in the laboratory. Majority of disease-causing gene mutations were uncommon in the general population, where dominant variations could be easily identified in certain disorders. The development of molecular, next generation sequencing (NGS) and cytogenetic techniques allowed to identify multiple genetic mutations leading to diseases. Using of the accurate multivariate diagnosis of diseases would be essential for appropriate treatment of patients, genetic counseling and prevention strategies Recent findings: Abnormal genes play an extremely important role in the pathogenesis of neurodegenerative disorders of the nervous system. Many studies of genetic have clearly indicated that the molecular mechanisms underlying the etiology and pathogenesis of most neurodegenerative disorders until now. Mutation is necessary for life, while fidelity is necessary for DNA replication. Mistakes in DNA replication/transcription can cause cells to produce either too much or too little protein or a defective protein. Studies on mutations have revealed the normal functions of genes, messages, proteins, the causes of many diseases, and the variability of responses among individuals. Based on the presence of damaging variants, there are many genes have identified that associated with neurodegenerative disorders through to genetic analyses of patients. This declaration is interesting because also our previous analysis has shown that several types of neurodegenerative diseases associated with abnormal genes function have been well described, including Alzheimer’s disease (AD), front temporal dementia (FTD), amyotrophic lateral sclerosis (ALS), prion disease, and Parkinson’s disease (PD). Since the potential treatment strategies for these disorders may be more successful during the pre-clinical stages than in the actual clinical setup, accurate, simple, and affordable diagnostic methods are needed. A mutation can be defined as a sequence change in a test sample compared to the sequence of a reference standard. This has led to the development of methods for screening and detecting abnormal DNA, including techniques that detect previously described mutations(genotyping) and those that scan for mutations in a particular target region (mutation scanning). This review provides a broad overview of the range of currently available mutation detection techniques with special emphasis on neurodegenerative disorders in humans. We have discussed the methods used for detecting unknown mutations, such as ribonuclease, denaturing gradient-gel electrophoresis, carbodiimide, chemical cleavage, single-strand conformation polymorphism, heteroduplex, and sequencing. Furthermore, other diagnostic methods for testing mutations include allele-specific oligonucleotide hybridization; allele-specific amplification, ligation, primer extension, and the artificial introduction of restriction sites are also reviewed. In order to identify the mutation, the last of the work provides basic insights into some of the most popular in silico tools for splicing defect prediction from the viewpoint of end users.

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

Giau, Vo Van,Bagyinszky, Eva,Youn, Young Chul,An, Seong Soo A.,Kim, SangYun MDPI AG 2019 INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES Vol.20 No.19

<P>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.</P>