記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1101/2023.10.17.23297061

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掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder that is caused by the abnormal expansion of non-coding trinucleotide GGC repeats in NOTCH2NLC. NIID is clinically characterized by a broad spectrum of clinical presentations. To date, the relationship between expanded repeat lengths and clinical phenotype in patients with NIID remains unclear. Thus, we aimed to clarify the genetic and clinical spectrum and their association in patients with NIID. For this purpose, we genetically analyzed Japanese patients with adult-onset NIID with characteristic clinical and neuroimaging findings. Trinucleotide repeat expansions of NOTCH2NLC were examined by repeat-primed and amplicon-length PCR. In addition, long-read sequencing was performed to determine repeat size and sequence. The expanded GGC repeats ranging from 94 to 361 in NOTCH2NLC were found in all 15 patients. Two patients carried biallelic repeat expansions. There were marked heterogenous clinical and imaging features in NIID patients. Patients presenting with cerebellar ataxia or urinary dysfunction had a significantly larger GGC repeat size than those without. This significant association disappeared when these parameters were compared with the total trinucleotide repeat number. ARWMC score was significantly higher in patients who had a non-glycine-type trinucleotide interruption within expanded poly-glycine motifs than in those with a pure poly-glycine expansion. These results suggested that the repeat length and sequence in NOTCH2NLC may partly modify some clinical and imaging features of NIID.

DOI： 10.3390/brainsci13060955

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: CSF1R-related leukoencephalopathy is an adult-onset leukoencephalopathy caused by mutations in CSF1R. The present study aimed to explore the broader genetic spectrum of CSF1R-related leukoencephalopathy in association with clinical and imaging features. METHODS: Mutational analysis of CSF1R was performed for 100 consecutive patients with adult-onset leukoencephalopathy. Sequence and copy number variation (CNV) analyses of CSF1R were performed. The genomic ranges of the deletions were determined by long-read sequencing. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing the CSF1R mutants identified in this study. RESULTS: We identified CSF1R mutations in 15 patients, accounting for 15% of the adult-onset leukoencephalopathy cases. Seven novel and five previously reported CSF1R mutations were identified. The novel mutations, including three missense and one in-frame 3-bp deletion, were located in the tyrosine kinase domain (TKD) of CSF1R. Functional assays revealed that none of the novel mutations in the TKD showed autophosphorylation of CSF1R. We identified two partial deletions of CSF1R that resulted in the lack of the C-terminal region, including the distal TKD, in two patients. Variable clinical features including cognitive impairment, psychiatric symptoms, and gait disturbance were observed. Various degrees of the white matter lesions and corpus callosum abnormalities on MRI and characteristic calcifications on CT were observed as imaging features. CONCLUSIONS: Our results highlighted the importance of examining the CNV of CSF1R even when Sanger or exome sequencing reveal no CSF1R mutations. Genetic examination of sequences and CNV analyses of CSF1R are recommended for an accurate diagnosis of CSF1R-related leukoencephalopathy.

DOI： 10.1111/ene.15796

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

DOI： 10.1093/jnen/nlac120

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Ovid Technologies (Wolters Kluwer Health)  

Objectives

Leigh syndrome is a progressive encephalopathy characterized by symmetrical lesions in brain. This study aimed to investigate the clinicopathologic and genetic characteristics of a family with Leigh syndrome and hereditary neuropathy with liability to pressure palsy (HNPP).

Methods

Data from a Japanese family's clinical features, MRIs, muscle biopsy, and an autopsy were analyzed. A whole-exome sequence was performed, as well as real-time PCR analysis to determine copy number variations and Western blot analyses.

Results

The proband and her 2 siblings developed spastic paraplegia and mental retardation during childhood. The proband and her sister had peripheral neuropathy, whereas their father developed compression neuropathy. Leigh encephalopathy was diagnosed neuropathologically. Brain MRI revealed changes in cerebral white matter as well as multiple lesions in the brainstem and cerebellum. Muscle biopsy revealed type 2 fiber uniformity and decreased staining of cytochrome c oxidase. The COX10 missense mutation was identified through whole-exome sequence. A 1.4-Mb genomic deletion extending from intron 5 of COX10 to PMP22 was detected.

Discussion

These findings suggest that in this family, Leigh syndrome is associated with a mitochondrial respiratory chain complex IV deficiency caused by biallelic COX10 mutations coexisting with HNPP caused by heterozygous PMP22 deletion.

DOI： 10.1212/nxg.0000000000200030

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.17879/freeneuropathology-2022-4285

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Argyrophilic grain disease (AGD), progressive supranuclear palsy (PSP) and corticobasal degeneration are four-repeat (4R) tauopathies that develop in the presenium or later. Whether these diseases are associated with the occurrence of late-onset psychiatric disorders remains unclear. To facilitate the accumulation of clinicopathological findings regarding this issue, we here present a selected series of 11 cases that clinically developed psychotic disorder (n = 7; age at onset: 41-75 years), depressive disorder (n = 1; 49 years), bipolar disorder (n = 2; 32 and 37 years) and somatoform disorder (n = 1; 88 years), and had at least one pathological hallmark of these tauopathies. The mean age at death was 74.3 years. No case showed dementia, at least in the early stage of the course. Nine cases had AGD. Granular fuzzy astrocytes in the amygdala were noted in all AGD cases and one non-AGD case. Two AGD cases had tufted astrocytes (TAs) in the amygdala but not in the frontal cortex and striatum. Three AGD and two non-AGD cases had TAs in the frontal cortex and/or striatum but not in the amygdala. One AGD case had a small number of astrocytic plaques in the frontal cortex, striatum and globus pallidus. Only one case was diagnosed as atypical PSP according to the NINDS-PSP neuropathological criteria. No case had high-level Alzheimer's disease pathology, Lewy body disease or limbic-predominant age-related TDP-43 encephalopathy. Two cases had mild neuronal loss in the hippocampus and substantia nigra, respectively. Clinicopathological studies focusing especially on early changes of 4R tauopathies, as well as the development of surrogate markers of these diseases, may be necessary for better understanding of the pathogenic backgrounds of late-onset psychiatric disorders.

DOI： 10.1111/neup.12820

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Alzheimer’s disease (AD) is an age-related multifactorial neurodegenerative disorder. Advances in genome technology, including next generation sequencing have uncovered complex genetic effects in AD by analyzing both common and rare functional variants. Multiple lines of evidence suggest that the pathogenesis of AD is influenced by multiple genetic components rather than single genetic factor. Previous genetic studies on AD have predominantly included European ancestry cohorts; hence, the non-European population may be underrepresented, potentially leading to reduced diversity in AD genetic research. Additionally, ethnic diversity may result in dissimilar effects of genetic determinants in AD. APOE genotypes are a well-established genetic risk factor in AD, with the East Asian population having a higher risk of AD associated with the APOE ε4 allele. To date, seven genome-wide association studies (GWAS) have been conducted in East Asians, which report a total of 26 AD-associated loci. Several rare variants, including the p.H157Y variant in TREM2, and the p.G186R and p.R274W variants in SHARPIN are associated with risk of AD in East Asians. Extending genetic studies to diverse populations, including East Asians is necessary, which could yield more comprehensive insights into AD, and here we review the recent findings regarding the genetic determinants of AD from an East Asian perspective.

DOI： 10.1038/s10038-022-01050-z

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その他リンク： https://www.nature.com/articles/s10038-022-01050-z

記述言語：英語   掲載種別：研究論文（学術雑誌）  

While amyloid-β lies upstream of tau pathology in Alzheimer's disease, key drivers for other tauopathies, including progressive supranuclear palsy (PSP), are largely unknown. Various tau mutations are known to facilitate tau aggregation, but how the nonmutated tau, which most cases with PSP share, increases its propensity to aggregate in neurons and glial cells has remained elusive. Here, we identified genetic variations and protein abundance of filamin-A in the PSP brains without tau mutations. We provided in vivo biochemical evidence that increased filamin-A levels enhance the phosphorylation and insolubility of tau through interacting actin filaments. In addition, reduction of filamin-A corrected aberrant tau levels in the culture cells from PSP cases. Moreover, transgenic mice carrying human filamin-A recapitulated tau pathology in the neurons. Our data highlight that filamin-A promotes tau aggregation, providing a potential mechanism by which filamin-A contributes to PSP pathology.

DOI： 10.1126/sciadv.abm5029

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記述言語：英語  

DOI： 10.1111/ggi.14361

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

DOI： 10.1038/s43587-021-00158-9

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その他リンク： https://www.nature.com/articles/s43587-021-00158-9

記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: The AT(N) classification was proposed for categorising individuals according to biomarkers. However, AT(N) profiles may vary depending on the markers chosen and the target population. Methods: We stratified 177 individuals who participated in the Japanese Alzheimer's Disease Neuroimaging Initiative by AT(N) classification according to cerebrospinal fluid (CSF) biomarkers. We compared the frequency of AT(N) profiles between the classification using total tau and neurofilament light chain (NfL) as N markers (AT(N)tau and AT(N)NfL). Baseline characteristics, and longitudinal biological and clinical changes were examined between AT(N) profiles. Results: We found that 9% of cognitively unimpaired subjects, 49% of subjects with mild cognitive impairment, and 61% of patients with Alzheimer's disease (AD) dementia had the biological AD profile (ie, A+T+) in the cohort. The frequency of AT(N) profiles substantially differed between the AT(N)tau and AT(N)NfL classifications. When we used t-tau as the N marker (AT(N)tau), those who had T- were more frequently assigned to (N)-, whereas those who had T+were more frequently assigned to (N)+ than when we used NfL as the N marker (AT(N)NfL). During a follow-up, the AD continuum group progressed clinically and biologically compared with the normal biomarker group in both the AT(N)tau and AT(N)NfL classifications. More frequent conversion to dementia was observed in the non-AD pathological change group in the AT(N)tau classification, but not in the AT(N)NfL classification. Conclusions: AT(N)tau and AT(N)NfL in CSF may capture different aspects of neurodegeneration and provide a different prognostic value. The AT(N) classification aids in understanding the AD continuum biology in various populations.

DOI： 10.1136/bmjno-2022-000321

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIMS: Neuronal and glial inclusions comprising transactive response DNA-binding protein of 43 kDa (TDP-43) have been identified in the brains of patients with corticobasal degeneration (CBD), and a possible correlation between the presence of these inclusions and clinical phenotypes has been speculated. However, the significance of TDP-43 pathology in the pathomechanism of CBD has remained unclear. Here, we investigated the topographical relationship between TDP-43 inclusions and neuronal loss in CBD. METHODS: We estimated semi-quantitatively neuronal loss and TDP-43 pathology in the form of neuronal cytoplasmic inclusions (NCIs), astrocytic inclusions (AIs), oligodendroglial cytoplasmic inclusions (GCIs), and dystrophic neurites in 22 CNS regions in 10 patients with CBD. Then, the degree of correlation between the severity of neuronal loss and the quantity of each type of TDP-43 inclusion was assessed. We also investigated tau pathology in a similar manner. RESULTS: TDP-43 pathology was evident in nine patients. The putamen and globus pallidus were the regions most frequently affected (80%). NCIs were the most prominent form, and their quantity was significantly correlated with the severity of neuronal loss in more than half of the regions examined. The quantities of TDP-43 NCIs and tau NCIs were correlated in only a few regions. The number of regions where the quantities of TDP-43 AIs and GCIs were correlated with the severity of neuronal loss was apparently small in comparison with that of NCIs. CONCLUSIONS: TDP-43 alterations in neurons, not closely associated with tau pathology, may be involved in the pathomechanism underlying neuronal loss in CBD. There was a significant topographical correlation between neuronal cytoplasmic aggregation of TDP-43 and neuronal loss in CBD, suggesting that TDP-43 protein aberration might be associated with neuronal degeneration in CBD. There was no close correlation between the burden of TDP-43 and that of tau in neurons.

DOI： 10.1111/nan.12786

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia, and its pathogenesis is multifactorial. We previously reported a rare functional variant of SHARPIN (rs572750141, NP_112236.3:p.Gly186Arg) that was significantly associated with LOAD. In addition, several recent studies have suggested the potential role of SHARPIN in AD pathogenesis. In this study, we sought to identify additional functional variants of SHARPIN in Japanese population. Six highly deleterious variants of SHARPIN, comprising four missense variants, one frameshift variant, and one stop-gain variant were detected from whole-genome sequencing data for 180 patients with LOAD and 184 with mild cognitive impairment. One of these candidate variants (rs77359862, NP_112236.3:p.Arg274Trp) was significantly associated with an increased risk of LOAD in 5043 LOAD cases and 11984 controls (P = 0.0016, odds ratio = 1.43). Furthermore, this variant SHARPIN showed aberrant cellular localization and reduced the activation of NF-κB, a central mediator of inflammatory and immune responses. Further investigation of the physiologic role of SHARPIN may reveal the mechanism of onset of LOAD.

DOI： 10.1038/s10038-021-00987-x

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Familial dementia is a rare inherited disease involving progressive impairment of memory, thinking, and behavior. We report a novel heterozygous pathogenic variant (c.199G > A, p.Val67Ile) in the CIAO1 gene that appears to be co-segregated with Alzheimer's disease in a Japanese family. Biochemical analysis of CIAO1 protein revealed that the variant increases the interaction of CIAO1 with immature amyloid-β protein precursor (AβPP), but not mature or soluble AβPP, indicating plausible CIAO1 involvement in AβPP processing. Our study indicates that a heterozygous variant in the CIAO1 gene may be closely related to autosomal dominant familial dementia.

DOI： 10.3233/JAD-210706

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Amyloid-β (Aβ) accumulation in the brain triggers the pathogenic cascade for Alzheimer's disease (AD) development. The secretory protein FAM3C (also named ILEI) is a candidate for an endogenous suppressor of Aβ production. In this study, we found that FAM3C expression was transcriptionally downregulated in the AD brain. To determine the transcriptional mechanism of the human FAM3C gene, we delineated the minimal 5'-flanking sequence required for basal promoter activity. From a database search for DNA-binding motifs, expression analysis using cultured cells, and promoter DNA-binding assays, we identified SP1 and EBF1 as candidate basal transcription factors for FAM3C, and found that SMAD1 was a putative inducible transcription factor and KLF6 was a transcription repressor for FAM3C. Genomic deletion of the basal promoter sequence from HEK293 and Neuro-2a cells markedly reduced endogenous expression of FAM3C and abrogated SP1- or EBF1-mediated induction of FAM3C. Nuclear protein extracts from AD brains contained lower levels of SP1 and EBF1 than did those from control brains, although the relative mRNA levels of these factors did not differ significantly between the groups. Additionally, the ability of nuclear SP1 and EBF1 in AD brains to bind with the basal promoter sequence-containing DNA probe was reduced compared with the binding ability of these factors in control brains. Thus, the transcriptional downregulation of FAM3C in the AD brain is attributable to the reduced nuclear levels and genomic DNA binding of SP1 and EBF1. An expressional decline in FAM3C may be a risk factor for Aβ accumulation and eventually AD development.

DOI： 10.1093/hmg/ddab226

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

前頭側頭型認知症(FTD)とレビー小体型認知症(DLB)は、代表的な非アルツハイマー型認知症である。FTDは前頭葉および側頭葉に神経変性が生じ、行動異常や失語など多彩な臨床症状を呈する。DLBは変動する認知障害、幻視、レム睡眠行動異常、パーキンソニズムを中核症状とする。病型により脳内に蓄積するタンパク質が異なっており、FTD患者脳ではタウ陽性あるいはTDP-43陽性の封入体が認められる。DLBではαシヌクレイン陽性のレビー小体が認められる。こうした病理像の違いが生じる一因として、発症に関連する遺伝子が異なることがあげられる。本稿では、FTDとDLBのゲノム解析に関する最近の知見を紹介し、この領域のゲノム医療を展望する。(著者抄録)

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掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

<title>Abstract</title>Alzheimer’s disease (AD) has no cure, but early detection and risk prediction could allow earlier intervention. Genetic risk factors may differ between ethnic populations. To discover novel susceptibility loci of AD in the Japanese population, we conducted a genome-wide association study (GWAS) with 3962 AD cases and 4074 controls. Out of 4,852,957 genetic markers that passed stringent quality control filters, 134 in nine loci, including <italic>APOE</italic> and <italic>SORL1</italic>, were convincingly associated with AD. Lead SNPs located in seven novel loci were genotyped in an independent Japanese AD case–control cohort. The novel locus <italic>FAM47E</italic> reached genome-wide significance in a meta-analysis of association results. This is the first report associating the <italic>FAM47E</italic> locus with AD in the Japanese population. A trans-ethnic meta-analysis combining the results of the Japanese data sets with summary statistics from stage 1 data of the International Genomics of Alzheimer’s Project identified an additional novel susceptibility locus in <italic>OR2B2</italic>. Our data highlight the importance of performing GWAS in non-European populations.

DOI： 10.1038/s41398-021-01272-3

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その他リンク： http://www.nature.com/articles/s41398-021-01272-3

掲載種別：研究論文（学術雑誌）   出版者・発行元：Cold Spring Harbor Laboratory  

<title>Abstract</title>In amyotrophic lateral sclerosis (ALS), TAR DNA-binding protein 43 (TDP-43) forms aggregates in the motor cortex of the aging brain. This aggregate formation may be triggered by the increase in TDP-43 levels with aging. However, the amount of TDP-43 is autoregulated by the alternative splicing of the <italic>TARDBP</italic> 3’UTR, and its relationship with aging remains unresolved. Since DNA methylation is altered during aging, we hypothesized that 3’UTR methylation is also altered in the aging motor cortex, disrupting this autoregulatory system and increasing TDP-43 levels. We found that DNA demethylation in the autoregulatory region of TDP-43 reduced alternative splicing and increased TDP-43 expression. Furthermore, in the human motor cortex, we found that this region was demethylated with age and that the expression of TDP-43 increased. The dysregulation of TDP-43 autoregulation by age-related DNA demethylation in the motor cortex may explain the contribution of aging and system selectivity in ALS.

DOI： 10.1101/2021.01.13.426599

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：{MDPI} {AG}  

Ribosomal RNA (rRNA), the most abundant non-coding RNA species, is a major component of the ribosome. Impaired ribosome biogenesis causes the dysfunction of protein synthesis and diseases called "ribosomopathies," including genetic disorders with cancer risk. However, the potential role of rRNA gene (rDNA) alterations in cancer is unknown. We investigated germline and somatic single-nucleotide variants (SNVs) in the rDNA promoter region (positions -248 to +100, relative to the transcription start site) in 82 lung adenocarcinomas (LUAC). Twenty-nine tumors (35.4%) carried germline SNVs, and eight tumors (9.8%) harbored somatic SNVs. Interestingly, the presence of germline SNVs between positions +1 and +100 (n = 12; 14.6%) was associated with significantly shorter recurrence-free survival (RFS) and overall survival (OS) by univariate analysis (p < 0.05, respectively), and was an independent prognostic factor for RFS and OS by multivariate analysis. LUAC cell line PC9, carrying rDNA promoter SNV at position +49, showed significantly higher ribosome biogenesis than H1650 cells without SNV. Upon nucleolar stress induced by actinomycin D, PC9 retained significantly higher ribosome biogenesis than H1650. These results highlight the possible functional role of SNVs at specific sites of the rDNA promoter region in ribosome biogenesis, the progression of LUAC, and their potential prognostic value.

DOI： 10.3390/cells9112409

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T- segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be derived from distant sites on the same chromosome. Due to lack of proper methodology, however, no direct evidence has been described so far. The beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. Here we devise a genome-wide mapping technique (eTIP-seq) for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It revealed that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that topo IIβ acts on crossovers to unknot the intertwined DSP sites, leading to chromatin decondensation.

DOI： 10.1038/s41598-020-75004-w

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40478-020-01008-2

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記述言語：日本語   出版者・発行元：医歯薬出版(株)  

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Wiley  

Vanishing white matter disease (VWM) is an autosomal recessive neurological disorder caused by mutation(s) in any subunit of eukaryotic translation initiation factor 2B (eIF2B), an activator of translation initiation factor eIF2. VWM occurs with mutation of the genes encoding eIF2B subunits (EIF2B1, EIF2B2, EIF2B3, EIF2B4, and EIF2B5). However, little is known regarding the underlying pathogenetic mechanisms or how to treat patients with VWM. Here we describe the identification and detailed analysis of a new spontaneous mutant mouse harboring a point mutation in the Eif2b5 gene (p.Ile98Met). Homozygous Eif2b5I98M mutant mice exhibited a small body, abnormal gait, male and female infertility, epileptic seizures, and a shortened lifespan. Biochemical analyses indicated that the mutant eIF2B protein with the Eif2b5I98M mutation decreased guanine nucleotide exchange activity on eIF2, and the level of the endoplasmic reticulum stress marker activating transcription factor 4 was elevated in the 1-month-old Eif2b5I98M brain. Histological analyses indicated up-regulated glial fibrillary acidic protein immunoreactivity in the astrocytes of the Eif2b5I98M forebrain and translocation of Bergmann glia in the Eif2b5I98M cerebellum, as well as increased mRNA expression of an endoplasmic reticulum stress marker, C/EBP homologous protein. Disruption of myelin and clustering of oligodendrocyte progenitor cells were also indicated in the white matter of the Eif2b5I98M spinal cord at 8 months old. Our data show that Eif2b5I98M mutants are a good model for understanding VWM pathogenesis and therapy development. Cover Image for this issue: doi: 10.1111/jnc.14751.

DOI： 10.1111/jnc.14887

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40478-020-00945-2

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The aberrant metabolism of amyloid β peptide (Aβ) has been implicated in the etiology of Alzheimer disease (AD). Aβ is produced via the sequential cleavage of amyloid precursor protein (APP) by β- and γ-secretases. However, the precise regulatory mechanism of Aβ generation still remains unclear. To gain a better understanding of the molecular mechanism of Aβ production, we established a genetic screening method based on the CRISPR/Cas9 system to identify novel regulators of Aβ production. We successfully identified calcium and integrin-binding protein 1 (CIB1) as a potential negative regulator of Aβ production. The disruption of Cib1 significantly upregulated Aβ levels. In addition, immunoprecipitation experiments demonstrated that CIB1 interacts with the γ-secretase complex. Moreover, the disruption of Cib1 specifically reduced the cell-surface localization of mature Nicastrin (Nct), which is a component of the γ-secretase complex, without changing the intrinsic activity of γ-secretase. Finally, we confirmed using the single-cell RNA-seq data in human that CIB1 mRNA level in neuron was decreased in the early stage of AD. Taken together, our results indicate that CIB1 regulates Aβ production via controlling the subcellular localization of γ-secretase, suggesting CIB1 is involved in the development of AD.

DOI： 10.1096/fj.201902966RR

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The molecular biological mechanisms of Alzheimer's disease (AD) involve disease-associated crosstalk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available as well as our own gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were increased specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

DOI： 10.1093/hmg/ddz320

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記述言語：日本語   出版者・発行元：新潟医学会  

認知症の半数以上を占めるアルツハイマー病(Alzheimer's Disease:AD)はガン、糖尿病、高血圧などと同じく「ありふれた疾患」である。個々人の遺伝的素因を背景に環境要因(ライフスタイル、食生活、運動など)が加わって潜行性に発症し、緩徐に不可逆的に進行する。遺伝要因、環境要因の寄与率はそれぞれおよそ6割、4割を占めることがこれまでに明らかにされている。マイクロサテライトマーカーを用いた連鎖解析、ジーンチップによるゲノムワイド関連解析(Genome-Wide Association Study:GWAS)、次世代シーケンサーを駆使したターゲットリシーケンシング、全エクソーム解析、全ゲノム解析によって、家族性AD、孤発性ADに関与する遺伝子や病的・保護的バリアントが続々と見出されている。1990年代に若年性の家族性ADの原因遺伝子として報告されたAPP、PSEN1、PSEN2のバリアント解析は、今では臨床診断を確定する際に極めて有効である。同じく1990年代に孤発性ADの感受性遺伝子として初めて報告されたAPOEは、その周辺領域を含めゲノムワイドなレベルで非常に強力にADと関連することが2000年代のGWASで確証された。認知機能、脳画像、液性バイオマーカー(アミロイドベータタンパクやタウタンパク)などの量的形質とも強い関連を示す。そのため孤発性ADの病態を解明し、その治療戦略を考える上で無視できない重要な感受性遺伝子としての地位が確立した。これまでのところ、APOEのインパクトを凌ぐAD感受性遺伝子やバリアントは報告されていない。本稿では講演内容の一部を抜粋し、ADの原因遺伝子、感受性遺伝子にフォーカスして論を進める。この機会にADの遺伝要因に関する理解を深め、今後の更なる研究展開に向けた糧としたい。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00990&link_issn=&doc_id=20201223030003&doc_link_id=http%3A%2F%2Fhdl.handle.net%2F10191%2F00052024&url=http%3A%2F%2Fhdl.handle.net%2F10191%2F00052024&type=%90V%8A%83%91%E5%8Aw%81F%90V%8A%83%91%E5%8Aw%8Aw%8Fp%83%8A%83%7C%83W%83g%83%8A_Nuar&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80230_3.gif

記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   出版者・発行元：(一社)日本神経学会  

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Next generation sequencing (NGS) technology has dramatically influenced the field of omics studies, such as genomics and transcriptomics. It is now possible to access a significant number of previously known and novel genomic variants through NGS. Although the effective manipulation and accurate interpretation of the inordinate amount of data may pose a considerable challenge, it enables us to identify specific genes responsible for causing or influencing the susceptibility to a plethora of diseases. Alzheimer's disease (AD) is the most common etiology of dementia in the elderly (approximately 60-70%). The current research trend of AD genetics focuses on the analysis of rare variants (allelic frequency <1%) instead of common variants (allelic frequency >1%) to identify AD-associated genes/variants. A number of genes (such as TREM2, ABCA7, SORL1) that carry rare pathogenic variants have reportedly conferred susceptibility to AD with stronger genetic risk effects (odds ratio >2.0). Here, we are going to introduce a small part of the latest many attractive findings about AD genetic researches.

DOI： 10.11477/mf.1416201406

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Genome-wide association studies (GWASs) have identified single-nucleotide polymorphisms (SNPs) that may be genetic factors underlying Alzheimer's disease (AD). However, how these AD-associated SNPs (AD SNPs) contribute to the pathogenesis of this disease is poorly understood because most of them are located in non-coding regions, such as introns and intergenic regions. Previous studies reported that some disease-associated SNPs affect regulatory elements including enhancers. We hypothesized that non-coding AD SNPs are located in enhancers and affect gene expression levels via chromatin loops. METHODS: To characterize AD SNPs within non-coding regions, we extracted 406 AD SNPs with GWAS p-values of less than 1.00 × 10- 6 from the GWAS catalog database. Of these, we selected 392 SNPs within non-coding regions. Next, we checked whether those non-coding AD SNPs were located in enhancers that typically regulate gene expression levels using publicly available data for enhancers that were predicted in 127 human tissues or cell types. We sought expression quantitative trait locus (eQTL) genes affected by non-coding AD SNPs within enhancers because enhancers are regulatory elements that influence the gene expression levels. To elucidate how the non-coding AD SNPs within enhancers affect the gene expression levels, we identified chromatin-chromatin interactions by Hi-C experiments. RESULTS: We report the following findings: (1) nearly 30% of non-coding AD SNPs are located in enhancers; (2) eQTL genes affected by non-coding AD SNPs within enhancers are associated with amyloid beta clearance, synaptic transmission, and immune responses; (3) 95% of the AD SNPs located in enhancers co-localize with their eQTL genes in topologically associating domains suggesting that regulation may occur through chromatin higher-order structures; (4) rs1476679 spatially contacts the promoters of eQTL genes via CTCF-CTCF interactions; (5) the effect of other AD SNPs such as rs7364180 is likely to be, at least in part, indirect through regulation of transcription factors that in turn regulate AD associated genes. CONCLUSION: Our results suggest that non-coding AD SNPs may affect the function of enhancers thereby influencing the expression levels of surrounding or distant genes via chromatin loops. This result may explain how some non-coding AD SNPs contribute to AD pathogenesis.

DOI： 10.1186/s12920-019-0574-8

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Variants in the APOE gene region may explain ethnic differences in the association of Alzheimer's disease (AD) with ε4. Ethnic differences in allele frequencies for three APOE region SNPs (single nucleotide polymorphisms) were identified and tested for association in 19,398 East Asians (EastA), including Koreans and Japanese, 15,836 European ancestry (EuroA) individuals, and 4985 African Americans, and with brain imaging measures of cortical atrophy in sub-samples of Koreans and EuroAs. Among ε4/ε4 individuals, AD risk increased substantially in a dose-dependent manner with the number of APOE promoter SNP rs405509 T alleles in EastAs (TT: OR (odds ratio) = 27.02, p = 8.80 × 10-94; GT: OR = 15.87, p = 2.62 × 10-9) and EuroAs (TT: OR = 18.13, p = 2.69 × 10-108; GT: OR = 12.63, p = 3.44 × 10-64), and rs405509-T homozygotes had a younger onset and more severe cortical atrophy than those with G-allele. Functional experiments using APOE promoter fragments demonstrated that TT lowered APOE expression in human brain and serum. The modifying effect of rs405509 genotype explained much of the ethnic variability in the AD/ε4 association, and increasing APOE expression might lower AD risk among ε4 homozygotes.

DOI： 10.3390/jcm8081236

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Late-onset Alzheimer's disease (LOAD), the most common form of dementia, results from complicated interactions among multiple environmental and genetic factors. Despite recent advances in genetic analysis of LOAD, more than half of the heritability for the disease remains unclear. Although genetic studies in Caucasians found rare risk variants for LOAD with large effect sizes, these variants are hardly detectable in the Japanese population. METHODS: To identify rare variants possibly explaining part of the genetic architecture for LOAD in Japanese people, we performed whole-exome sequencing analyses of 202 LOAD individuals without the APOE ε4 risk allele, a major genetic factor for LOAD susceptibility. We also implemented in vitro functional analyses of the variant(s) to reveal possible functions associated with LOAD risk. RESULTS: Via step-by-step selection of whole-exome variants, we found seven candidate risk variants. We then conducted a case-control association study in a large Japanese cohort consisting of 4563 cases and 16,459 controls. We finally identified a rare nonsynonymous variant, rs572750141 (NM_030974.3:p.Gly186Arg), in SHARPIN that was potentially associated with increased risk of LOAD (corrected P = 8.05 × 10- 5, odds ratio = 6.1). The amino acid change in SHARPIN resulted in aberrant cellular localization of the variant protein and attenuated the activation of NF-κB, a central mediator of inflammatory and immune responses. CONCLUSIONS: Our work identified a rare functional SHARPIN variant as a previously unknown genetic risk factor for LOAD. The functional alteration in SHARPIN induced by the rare coding variant is associated with an attenuated inflammatory/immune response that may promote LOAD development.

DOI： 10.1186/s10020-019-0090-5

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出版者・発行元：Cold Spring Harbor Laboratory  

<title>Abstract</title><sec><title>Background</title>Type II DNA topoisomerases (topo II) flip the spatial positions of two DNA duplexes, called G- and T-segments, by a cleavage-passage-resealing mechanism. In living cells, these DNA segments can be placed far from each other on the same chromosome. However, no direct evidence for this to occur has been described so far due to lack of proper methodology.

</sec><sec><title>Results</title>The beta isoform of topo II (topo IIβ) is essential for transcriptional regulation of genes expressed in the final stage of neuronal differentiation. To elucidate the enzyme’s role in the process, here we devise a genome-wide mapping technique for topo IIβ target sites that can measure the genomic distance between G- and T-segments. It became clear that the enzyme operates in two distinctive modes, termed proximal strand passage (PSP) and distal strand passage (DSP). PSP sites are concentrated around transcription start sites, whereas DSP sites are heavily clustered in small number of hotspots. While PSP represent the conventional topo II targets that remove local torsional stresses, DSP sites have not been described previously. Most remarkably, DSP is driven by the pairing between homologous sequences or repeats located in a large distance. A model-building approach suggested that the DSP sites are intertwined or knotted and topo IIβ is engaged in unknotting reaction that leads to chromatin decondensation and gene regulation.

</sec><sec><title>Conclusions</title>When combined with categorized gene expression analysis, the model-based prediction of DSP sites reveals that DSP is one of the key factors for topo IIβ-dependency of neuronal gene regulation.

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DOI： 10.1101/484956

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by mutations in CSF1R. Pathogenic mutations in exons 12-22 including coding sequence of the tyrosine kinase domain (TKD) of CSF1R were previously identified. We aimed to identify CSF1R mutations in patients who were clinically suspected of having ALSP and to determine the pathogenicity of novel CSF1R variants. METHODS: Sixty-one patients who fulfilled the diagnostic criteria of ALSP were included in this study. Genetic analysis of CSF1R was performed for all the coding exons. The haploinsufficiency of CSF1R was examined for frameshift mutations by RT-PCR. Ligand-dependent autophosphorylation of CSF1R was examined in cells expressing CSF1R mutants. RESULTS: We identified ten variants in CSF1R including two novel frameshift, five novel missense, and two known missense mutations as well as one known missense variant. Eight mutations were located in TKD. One frameshift mutation (p.Pro104LeufsTer8) and one missense variant (p.His362Arg) were located in the extracellular domain. RT-PCR analysis revealed that the frameshift mutation of p.Pro104LeufsTer8 caused nonsense-mediated mRNA decay. Functional assay revealed that none of the mutations within TKD showed autophosphorylation of CSF1R. The p.His362Arg variant located in the extracellular domain showed comparable autophosphorylation of CSF1R to the wild type, suggesting that this variant is not likely pathogenic. CONCLUSIONS: The detection of the CSF1R mutation outside of the region-encoding TKD may extend the genetic spectrum of ALSP with CSF1R mutations. Mutational analysis of all the coding exons of CSF1R should be considered for patients clinically suspected of having ALSP.

DOI： 10.1007/s00415-018-9017-2

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Deposition of amyloid-β (Aβ) as senile plaques is one of the pathological hallmarks in the brains of Alzheimer's disease (AD) patients. In addition, glial activation has been found in AD brains, although the precise pathological role of astrocytes remains unclear. Here, we identified kallikrein-related peptidase 7 (KLK7) as an astrocyte-derived Aβ degrading enzyme. Expression of KLK7 mRNA was significantly decreased in the brains of AD patients. Ablation of Klk7 exacerbated the thioflavin S-positive Aβ pathology in AD model mice. The expression of Klk7 was upregulated by Aβ treatment in the primary astrocyte, suggesting that Klk7 is homeostatically modulated by Aβ-induced responses. Finally, we found that the Food and Drug Administration-approved anti-dementia drug memantine can increase the expression of Klk7 and Aβ degradation activity specifically in the astrocytes. These data suggest that KLK7 is an important enzyme in the degradation and clearance of deposited Aβ species by astrocytes involved in the pathogenesis of AD.

DOI： 10.15252/emmm.201708184

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

MicroRNAs (miRNAs) are attractive molecules to utilize as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD) because miRNAs are relatively stable in biofluid, including serum or plasma. To determine blood miRNA biomarkers for AD with next-generation sequencing genome-wide, we first surveyed 45 serum samples. These came from 27 AD patients and 18 controls (discovery set) that underwent autopsy within two weeks after their serum sampling and were neuropathologically diagnosed. We found that three miRNAs, hsa-miR-501-3p, hsa-let-7f-5p, and hsa-miR-26b-5p, were significantly deregulated between the AD samples and the controls. The deregulation for hsa-miR-501-3p was further confirmed by quantitative reverse transcription polymerase chain reaction (PCR) in a validation set composed of 36 clinically diagnosed AD patients and 22 age-matched cognitively normal controls with a sensitivity and specificity of 53% and 100%, respectively (area under the curve = 0.82). Serum hsa-miR-501-3p levels were downregulated in AD patients, and its lower levels significantly correlated with lower Mini-Mental State Examination scores. Contrary to its serum levels, we found that hsa-miR-501-3p was remarkably upregulated in the same donors' AD brains obtained at autopsy from the discovery set. The hsa-miR-501-3p overexpression in cultured cells, which mimicked the hsa-miR-501-3p upregulation in the AD brains, induced significant downregulation of 128 genes that overrepresented the Gene Ontology terms, DNA replication, and the mitotic cell cycle. Our results suggest that hsa-miR-501-3p is a novel serum biomarker that presumably corresponds to pathological events occurring in AD brains.

DOI： 10.1186/s40478-017-0414-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.jns.2016.11.032

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Juvenile brain has a unique time window, or critical period, in which neuronal circuits are remodeled by experience. Mounting evidence indicates the importance of neuronal circuit rewiring in various neurodevelopmental disorders of human cognition. We previously showed that Otx2 homeoprotein, essential for brain formation, is recaptured during postnatal maturation of parvalbumin-positive interneurons (PV cells) to activate the critical period in mouse visual cortex. Cortical Otx2 is the only interneuron-enriched transcription factor known to regulate the critical period, but its downstream targets remain unknown. Here, we used ChIP-seq (chromatin immunoprecipitation sequencing) to identify genome-wide binding sites of Otx2 in juvenile mouse cortex, and interneuron-specific RNA-seq to explore the Otx2-dependent transcriptome. Otx2-bound genes were associated with human diseases such as schizophrenia as well as critical periods. Of these genes, expression of neuronal factors involved in transcription, signal transduction and mitochondrial function was moderately and broadly affected in Otx2-deficient interneurons. In contrast to reported binding sites in the embryo, genes encoding potassium ion transporters such as KV3.1 had juvenile cortex-specific binding sites, suggesting that Otx2 is involved in regulating fast-spiking properties during PV cell maturation. Moreover, transcripts of oxidative resistance-1 (Oxr1), whose promoter has Otx2 binding sites, were markedly downregulated in Otx2-deficient interneurons. Therefore, an important role of Otx2 may be to protect the cells from the increased oxidative stress in fast-spiking PV cells. Our results suggest that coordinated expression of Otx2 targets promotes PV cell maturation and maintains its function in neuronal plasticity and disease.

DOI： 10.3389/fnins.2017.00307

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Numerous epidemiological studies have shown that the apolipoprotein E gene (APOE) is a strong genetic risk factor for Alzheimer's disease (AD) among people from various ethnic backgrounds. ApoE occurs as three isoforms that differ at two amino acids residues (112 and 158): ApoE ε2, ε3, and ε4. The ε4 allele is responsible for a genetic predisposition to AD, increasing the risk of AD by approximately 4-fold compared to the common ε3 allele. In contrast, the ε2 allele shows a protective effect against AD. APOE ε4 is known to affect the age at onset of AD in a dose-dependent manner. In addition to the role of genetic risk, increasing evidence suggests that the substantial effects of APOE genotypes on cognitive function, imaging and biomarker findings, have been reported in cognitively normal individuals in an age-dependent manner. A high frequency of amyloid deposition among cognitively normal, aged individuals carrying the APOE ε4 allele has been demonstrated. This suggests that APOE ε4 facilitates amyloid deposition during the very early phase of AD pathogenesis. Preventive intervention by using disease-modifying drugs is now being investigated through an exploratory clinical trial for the cognitively normal, aged individuals with the APOE ε4 allele.

DOI： 10.11477/mf.1416200498

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Mutations in APP, PSEN1 and PSEN2 as the genetic causes of familial Alzheimer's disease (FAD) have been found in various ethnic populations. A substantial number of FAD pedigrees with mutations have been reported in the Japanese population; however, it remains unclear whether the genetic and clinical features of FAD in the Japanese population differ from those in other populations. To address this issue, we conducted a systematic review and meta-analysis of Japanese FAD and frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) by literature search. Using this analysis, we identified 39 different PSEN1 mutations in 140 patients, 5 APP mutations in 35 patients and 16 MAPT mutations in 84 patients. There was no PSEN2 mutation among Japanese patients. The age at onset in Japanese FAD patients with PSEN1 mutations was significantly younger than that in patients with APP mutations. Kaplan-Meier analysis revealed that patients with MAPT mutations showed a shorter survival than patients with PSEN1 or APP mutations. Patients with mutations in different genes exhibit characteristic clinical presentations, suggesting that mutations in causative genes may modify the clinical presentations. By collecting and cataloging genetic and clinical information on Japanese FAD and FTDP-17, we developed an original database designated as Japanese Familial Alzheimer's Disease Database, which is accessible at http://alzdb.bri.niigata-u.ac.jp/.

DOI： 10.1038/jhg.2015.15

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掲載種別：研究論文（学術雑誌）  

DOI： 10.1038/tp.2014.35

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記述言語：日本語   掲載種別：研究論文（学術雑誌）  

Alzheimer's disease (AD) is the most common type of dementia in the elderly and has multiple causes. The amyloid precursor protein (APP), presenilin1 (PSEN1), and presenilin2 (PSEN2) genes were identified as causative genes in a small number of families with autosomal dominant early-onset forms of AD (ADEOAD). However, many AD cases are sporadic and the late-onset type, which develops after 65 years of age. The apolipoprotein gene (APOE) is the strongest risk gene for sporadic and familial late-onset AD (LOAD) regardless of ethnicity. Since about half of the patients with LOAD do not have the risk allele (ε4) of APOE and λs (=5) is larger than λsAPOE (=2.5), risk genes other than APOE are expected to be involved in LOAD. Based on the common disease-common variants hypothesis, genome-wide association studies (GWAS) were performed tenaciously to identify genes related to AD. However, even large-scale GWAS with relatively high frequency of single nucleotide polymorphisms did not reveal any additional risk genes with nearly equal power of APOE. Recently, individual whole genome or whole exon sequencing data obtained using next-generation sequencers have become available. Mutations in the causative genes of ADEOAD have been also observed in both familial LOAD and sporadic EOAD. Furthermore, new causative genes have been identifies in some families by whole genome or exome analyses. Considering the new common disease-rare variants hypothesis, personal genome sequence analysis is a potential strategy for identifying AD risk or protective genes.

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記述言語：日本語   出版者・発行元：(株)ワールドプランニング  

アルツハイマー病(AD)は糖尿病などと同じく「ありふれた疾患」である。遺伝的素因を背景にさまざまな環境要因が加わって潜行性に発症し、緩徐に不可逆的に進行する。ADは認知症全体のおよそ6〜7割を占め、最も頻度が高い。加齢が最大のリスク要因ではあるが、遺伝要因の寄与率はおよそ6割と見積もられている。これは、先天的な疾患感受性要因としてバリアント情報を軽視できないことを意味している。本稿では、AD感受性遺伝子について最新の知見を概説した。(著者抄録)

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記述言語：日本語  

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その他リンク： https://search.jamas.or.jp/link/ui/2019250471

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記述言語：日本語   出版者・発行元：(株)中外医学社  

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記述言語：日本語   出版者・発行元：(株)羊土社  

数万人規模のゲノムワイド関連解析によりアルツハイマー病(Alzheimer&#039;s disease:AD)に関するリスク遺伝子の探索が行われたが、APOEに匹敵するエフェクトをもつ感受性遺伝子は検出されなかった。しかし、次世代シークエンサーによる網羅的なゲノム情報が効率的に得られるようになり、APOEに匹敵するADリスク遺伝子が同定されている。これまで同定が困難であった低頻度のレアバリアントが、AD発症の新たなリスクとなることが判明している。一方で、防御的効果を有するレアバリアントが見出されており、ADの先制医療の観点から注目されている。本稿ではAPOEに加え、次世代シークエンサー(NGS)により同定されたAD関連遺伝子を紹介し、AD発症の危険因子と防御因子の両面からAD病態を再考する。(著者抄録)

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記述言語：日本語   出版者・発行元：フジメディカル出版  

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その他リンク： http://search.jamas.or.jp/link/ui/2017235541

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：医歯薬出版  

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その他リンク： http://search.jamas.or.jp/link/ui/2016194797

記述言語：日本語   出版者・発行元：アークメディア  

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その他リンク： http://search.jamas.or.jp/link/ui/2016211674

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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記述言語：日本語   出版者・発行元：(一社)日本認知症学会  

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