研究者詳細 - 山下　徹

論文 - 山下　徹

分割表示 332 件中 181 - 200 件目／全件表示 >>

Case of myasthenia gravis and Lambert-Eaton myasthenic syndrome overlap syndrome accompanied by autoimmune encephalitis and cerebellar ataxia with multiple neuronal antibodies

Yumiko Nakano, Emi Nomura, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 5 ( 5 ) 152 - 154 2017年9月

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

A 72-year-old woman developed a subacute series of encephalitis, cerebellar ataxia, and combined symptoms of both myasthenia gravis and Lambert-Eaton myasthenic syndrome. Seven different neuronal antibodies were detected for Hu, glutamic acid decarboxylase, acetylcholine receptor, P/Q-type voltage-gated calcium-channels, Zic4, Titin and SOX1 in her serum with intrathecal synthesis of glutamic acid decarboxylase antibodies. Although she showed classical manifestations with onconeural antibodies, she was diagnosed with not paraneoplastic but autoimmune neurological syndrome because of no underlying tumor and good response to immunotherapies. The present case is very unique and rare for complex neurological disorders including myasthenia gravis and Lambert-Eaton myasthenic syndrome overlap syndrome with multiple neuronal antibodies.

DOI： 10.1111/ncn3.12134

Different Characteristics of Anterior and Posterior Branch Atheromatous Diseases with or without Early Neurologic Deterioration. 査読国際誌

Yoshiaki Takahashi, Toru Yamashita, Ryuta Morihara, Yumiko Nakano, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Yasuhiro Manabe, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 26 ( 6 ) 1314 - 1320 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Among several types of ischemic stroke (IS), branch atheromatous disease (BAD) is known to be the leading cause of disability. METHODS: A total of 1919 patients with acute IS were retrospectively analyzed, and BAD patients were classified into anterior or posterior BAD, depending on the responsible vascular territories. These patients were further subcategorized with or without early neurologic deterioration (END or no-END). RESULTS: Of all IS patients, 14.3% had BAD, and 202 patients (73.7%) were further classified as anterior BAD and 72 patients (26.3%) as posterior BAD. The prevalence of diabetes mellitus and END was significantly higher in posterior than in anterior BAD (44.4% vs 26.4%, P < .01; 18.1% vs 5.4%, P < .01, respectively). Posterior BAD showed a higher proportion of female patients and an older age (69.2% vs 39.0%, P < .05; 79.1 ± 7.7 vs 70.5 ± 10.7, P < .01, respectively) in END than in no-END. The modified Rankin Scale was worse in posterior BAD at 90 days (2.5 ± 1.6, P < .01) than in anterior BAD (1.6 ± 1.4). CONCLUSIONS: Our present study shows that posterior BAD is a worse clinical outcome than anterior BAD, with more vascular risk factors. Older female patients with posterior BAD showed a higher risk of END, leading to a worse clinical outcome.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.02.001

Neuroprotective Effects of a Novel Antioxidant Mixture Twendee X in Mouse Stroke Model. 査読国際誌

Momoko Kusaki, Yasuyuki Ohta, Haruhiko Inufusa, Toru Yamashita, Ryuta Morihara, Yumiko Nakano, Xia Liu, Jingwei Shang, Feng Tian, Yusuke Fukui, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association 26 ( 6 ) 1191 - 1196 2017年6月

記述言語：英語掲載種別：研究論文（学術雑誌）

BACKGROUND: Oxidative stress and inflammation are important aggravating factors in acute ischemic stroke. METHODS: In the present study, the neuroprotective effects of a novel antioxidant mixture Twendee X containing multiple antioxidative ingredients, such as coenzyme Q10, ascorbic acid, and cystine, were evaluated. After the pretreatment of a vehicle or Twendee X (20 mg/kg/d) for 14 days, mice were subjected to transient middle cerebral artery occlusion for 60 minutes and further treated with vehicle or Twendee X for 1 or 5 days. RESULTS: Twendee X administration reduced the infarct size, and reduced oxidative stress markers such as 8-hydroxy-2'-deoxyguanosine, 4-hydroxy-2-nonenal, and Nε-(carboxymethyl) lysine (one of advanced glycation end products), as well as inflammatory markers such as ionized calcium binding adapter molecule-1, tumor necrosis factor-α, and monocyte chemotactic protein-1. CONCLUSIONS: In the present study, the neuroprotective effects of Twendee X were shown on transient middle cerebral artery occlusion mice via antioxidative and anti-inflammatory pathways, providing a potential of Twendee X as one preventive and therapeutic treatment.

DOI： 10.1016/j.jstrokecerebrovasdis.2017.01.003

Aberrant distributions of nuclear pore complex proteins in ALS mice and ALS patients. 査読国際誌

Jingwei Shang, Toru Yamashita, Yumiko Nakano, Ryuta Morihara, Xianghong Li, Tian Feng, Xia Liu, Yong Huang, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Koji Abe

Neuroscience 350 158 - 168 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

Nuclear pore complexes (NPCs) play important roles in traffic of molecules between the nucleus and cytoplasm, aberrant distributions of components of NPCs were demonstrated in C9orf72 amyotrophic lateral sclerosis (C9-ALS) patients, but it is elusive whether such abnormities are also the case with other cause of ALS disease. In the present study, we investigated the spatiotemporal distributions of RanGAP1 and 4 representative nucleoporins (GP210, NUP205, NUP107 and NUP50) of NPCs in human Cu/Zn superoxide dismutase-1 mutation transgenic (SOD1-Tg) mice and sporadic ALS patients. Compared with wild type (WT), these proteins displayed age-dependent and progressive nuclear precipitations, and cytoplasmic aberrant expressions in motor neurons of lumbar cord in SOD1-Tg mice from 10 to 18weeks (W). Double immunofluorescent analysis showed abnormal nuclear retention and apparent co-localizations of RanGAPl with NUP205 and NUP205 with NUPl07, meanwhile, GP210 with NUP205 mainly co-localized in the nuclear envelope (NE) of motor neurons. Furthermore, RanGAP1, GP210 and NUP50 showed similarly abnormal nuclear precipitations and cytoplasmic upregulations in SOD1-Tg mice and ALS patients, moreover, aberrant co-localizations of RanGAP1 with TDP-43 and NUP205 with TDP-43 were also observed in motor neurons. The present study indicated that the mislocalization of these proteins of NPCs may underlie the pathogenesis of ALS both in SOD1-Tg mice and human sporadic ALS patients, and these dysfunctions may be a fundamental pathway for ALS that is not specific only in C9-ALS but also in SOD1-ALS, which may be amenable to pharmacotherapeutic intervention.

DOI： 10.1016/j.neuroscience.2017.03.024

Factors related to continuous and discontinuous attendance at memory clinics 査読

N. Hishikawa, Y. Fukui, Y. Nakano, R. Morihara, M. Takemoto, K. Sato, T. Yamashita, Y. Ohta, K. Abe

European Journal of Neurology 24 ( 5 ) 673 - 679 2017年5月

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

Background and purpose: Few studies have examined why some patients with dementia stop attending medical consultations. We conducted a retrospective study to investigate factors associated with discontinuous clinic attendance. Methods: Participants were 988 patients with dementia from university hospital (UH) clinics and affiliated local hospital (LH) clinics. We compared continuous and discontinuous attenders on cognitive and affective functions and activities of daily living (ADL), and also compared UH and LH patients (UH: continuous, n = 176
discontinuous, n = 207
LH: continuous, n = 418
discontinuous, n = 187). Results: The total annual rate of discontinuation was 8.0%, and the mean period of attendance before discontinuation was 2.2 ± 2.4 years (UH, 2.8 ± 3.0
LH, 1.5 ± 1.3, P &lt
0.01). Scores for the Mini-Mental State Examination, Hasegawa Dementia Scale – Revised, Geriatric Depression Scale, apathy scale, Abe's behavioral and psychological symptoms of dementia (BPSD) score, and ADL were significantly worse in the discontinuous group than the continuous group for both UH and LH patients (P &lt
0.01). The best predictor of discontinuation was ADL decline (UH and LH) and Abe's BPSD score (UH). The most common reason for discontinuation was returning to the family doctor (39.1% for UH), and cessation of hospital attendance at their own discretion (35.3% for LH). Conclusions: We identified the main reasons for discontinuation of attendance as returning to the family doctor and cessation of hospital attendance at their own discretion. The best predictors of discontinuation were ADL decline and worsening BPSD. There were significant differences in discontinuation between UH and LH patients with dementia.

DOI： 10.1111/ene.13268

Clinical features of incidental mild cognitive impairment and dementia in a population-based study. 査読

Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Toru Yamashita, Yasuyuki Ohta, Koji Abe

Geriatrics & gerontology international 17 ( 5 ) 722 - 729 2017年5月

記述言語：英語掲載種別：研究論文（学術雑誌）

AIM: The number of people with dementia is rapidly increasing as populations around the world age. It is important to grasp the characteristic features of mild cognitive impairment (MCI) for early detection and prevention of dementia. METHODS: We examined 408 individuals recruited from a health checkup for metabolic syndrome, which comprised three groups: normal (n = 325), MCI (n = 55) and apparent cognitive decline (ACD; n = 28). We compared cognitive/affective functions and exercise/hobby habits with assessments of vascular risk factors and results from computerized touch-panel tests. RESULTS: Among the 408 individuals, 93.1% showed normal scores on the Mini-Mental State Examination, and 6.9% had ACD. Among the normal Mini-Mental State Examination participants, 14.5% had MCI (13.5% of all participants). The three groups of participants showed significant differences in age, education, systolic blood pressure, glycosylated hemoglobin and high-density lipoprotein cholesterol level. Even within the normal range, those in the MCI group showed significantly lower cognitive function than those in the normal group. Scores on the Geriatric Depression Scale were greater in the MCI group, and "day-night reversal" was worse in the ACD group. Scores on touch-panel screening tests were significantly worse in the MCI and ACD groups than in the normal group. Participants showed better cognitive and affective function if they exercised regularly or had hobbies. CONCLUSIONS: Incidental MCI and ACD had prevalences of 13.5% and 6.9%, respectively, in the population-based study. Participants with these conditions showed cognitive/affective decline and impairment on computerized touch-panel tests in relation to vascular risk factors and exercise/hobbies. Geriatr Gerontol Int 2017; 17: 722-729.

DOI： 10.1111/ggi.12778

Familial amyotrophic lateral sclerosis of the G37V-superoxide dismutase 1 mutation with a slow disease progression

Koh Tadokoro, Yasuyuki Ohta, Yoshiaki Takahashi, Toru Yamashita, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Koji Abe

NEUROLOGY AND CLINICAL NEUROSCIENCE 5 ( 3 ) 96 - 98 2017年5月

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

The majority of amyotrophic lateral sclerosis patients have the sporadic form, but 5-10% of those have familial amyotrophic lateral sclerosis. A total of 15-20% of familial amyotrophic lateral sclerosis patients have genetic mutations in the superoxide dismutase 1 gene. In 2012, Kobayashi et al. reported the first case of a familial amyotrophic lateral sclerosis patient carrying a G37V superoxide dismutase 1 mutation, who showed rapid progression and died within 1.2 years of onset from respiratory failure. In contrast, here we report the second case of familial amyotrophic lateral sclerosis carrying the G37V superoxide dismutase 1 mutation, showing a very slow progression, and his father and aunt also had longer disease durations from 4 to 6 years. Further clinical and biological studies will clarify the detailed pathological role of the G37V superoxide dismutase 1 mutation for amyotrophic lateral sclerosis.

DOI： 10.1111/ncn3.12123

Ataxic form of autosomal recessive PEX10-related peroxisome biogenesis disorders with a novel compound heterozygous gene mutation and characteristic clinical phenotype. 査読国際誌

Toru Yamashita, Jun Mitsui, Nobuyuki Shimozawa, Shigeo Takashima, Hiroshi Umemura, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Takashi Matsukawa, Hiroyuki Ishiura, Jun Yoshimura, Koichiro Doi, Shinichi Morishita, Shoji Tsuji, Koji Abe

Journal of the neurological sciences 375 424 - 429 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Peroxisome biogenesis factor 10 (PEX10) is involved in the import of peroxisomal matrix proteins, and the mutation of this gene causes 3 subtypes of peroxisome biogenesis disorders, namely Zellweger syndrome (severe), neonatal adrenoleukodystrophy (moderate) and an ataxic form (mild). Here, we report 3 siblings of the ataxic form with cerebellar ataxia, mild mental retardation, and 3 additional characteristic features: mydriasis, hyperreflexia and involuntary head movement. All 3 siblings are compound heterozygous for a previously reported mutation, c.2T>C (p.M1T), and a novel mutation, c.920G>A, causing a missense change (p.C307Y) located in the RING finger domain of PEX10. The present cases suggest that these PEX10 mutations involve not only cerebellar but also more multiple nervous systems including pupillary autonomic, pyramidal and extrapyramidal systems.

DOI： 10.1016/j.jns.2017.02.058

Flow-metabolism uncoupling in the cervical spinal cord of ALS patients. 査読国際誌

Toru Yamashita, Tetsuhiro Hatakeyama, Kota Sato, Yusuke Fukui, Nozomi Hishikawa, Yasuyuki Ohta, Yoshihiro Nishiyama, Nobuyuki Kawai, Takashi Tamiya, Koji Abe

Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 38 ( 4 ) 659 - 665 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease. In ALS, both glucose consumption and neuronal intensity reportedly decrease in the cerebral motor cortex when measured by positron emission tomography (PET). In this study, we evaluated cervical spinal glucose metabolism, blood flow, and neuronal intensity of 10 ALS patients with upper extremity (U/E) atrophy both with 18F-2-fluoro-2-deoxy-D-glucose (18F-FDG) PET and 11C-flumazenil (11C-FMZ) PET. On the ipsilateral side of C5 and T1 levels, 18F-FDG uptake increased significantly (*p < 0.05), and was correlated with the rate of progression of the ALS FRS-R-U/E score (R = 0.645, *p = 0.041). Despite this hyperglucose metabolism, the 11C-FMZ PET study did not show a coupled increase of spinal blood flow even though neuronal intensity did not decrease. These results indicate a strong correlation between hyperglucose metabolism and ALS progression alongside the uncoupling of flow-metabolism. This mechanism, which could result in subsequent motor neuronal death, may be a potential therapeutic target for ALS.

DOI： 10.1007/s10072-017-2823-y

Cognitive and affective functions associated with insomnia: a population-based study. 査読国際誌

Nozomi Hishikawa, Yusuke Fukui, Kota Sato, Yasuyuki Ohta, Toru Yamashita, Koji Abe

Neurological research 39 ( 4 ) 331 - 336 2017年4月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVES: The number of patients with insomnia is rapidly increasing as society ages. The influence of insomnia on cognitive, affective, and activities of daily living (ADL) functions has not been fully studied. METHODS: Participants were 142 residents of a local super-aged community who underwent health check-ups provided by the local government. Participants completed cognitive, affective and ADL function tests including the MMSE. We divided participants into two subgroups based on Athens Insomnia Scale (AIS) scores (AIS ≤3 and AIS ≥4) and compared cognitive, affective, and ADL functions by sex and age. RESULTS: Subjective insomnia (AIS ≥4) was found in 36.2% of participants and was more frequent in females than males. No differences were found in cognitive function between the AIS subgroups. For both sexes, Geriatric Depression Scale scores were significantly higher in the AIS ≥4 subgroup than the AIS ≤3 subgroup. Apathy Scale scores were significantly higher in males in the AIS ≥4 subgroup. Of the AIS subscales, 'sleepiness during the day' was significantly higher in females than males (**p < 0.01), especially in those aged ≥75 years (**p < 0.01). This group of older females also showed a significantly lower Trail Making Test scores (*p < 0.05). DISCUSSION: Insomnia was present in 36.2% of the population in a Japanese super-aged community. Those with insomnia showed more depressive symptoms (both sexes) and males showed more apathy. The most distinct characteristic of females aged ≥75 years was a high frequency of daytime sleepiness, possibly related to a decline in attention and executive function.

DOI： 10.1080/01616412.2017.1281200

Novel Therapeutic Transplantation of Induced Neural Stem Cells for Stroke. 査読国際誌

Toru Yamashita, Wentao Liu, Yoshiaki Matsumura, Ryosuke Miyagi, Yun Zhai, Momoko Kusaki, Nozomi Hishikawa, Yasuyuki Ohta, Sung Min Kim, Tae Hwan Kwak, Dong Wook Han, Koji Abe

Cell transplantation 26 ( 3 ) 461 - 467 2017年3月

記述言語：英語掲載種別：研究論文（学術雑誌）

Somatic cells can be directly converted into induced neural stem cells (iNSCs) by defined transcription factors. However, the therapeutic effect of undifferentiated iNSCs on ischemic stroke has not been demonstrated. In this study, we used a mouse model of transient middle cerebral artery occlusion (tMCAO). iNSCs (5 × 105) were injected directly into the ipsilateral striatum and cortex 24 h after tMCAO. Histological analysis was performed at 7 days, 28 days, and 8 months after tMCAO. We found that iNSC transplantation successfully improved the survival rate of stroke model mice with significant functional recovery from the stroke. The fate of engrafted iNSCs was that the majority of iNSCs had differentiated into astroglial cells but not into neural cells in both the sham-operated brain and the poststroke brain without forming a tumor up to 8 months after tMCAO. Our data suggest that the directly converted iNSCs can be regarded as a candidate of safe cell resource for transplantation therapy in patients suffering from ischemic stroke.

DOI： 10.3727/096368916X692988

A patient with slowly progressive adult-onset nemaline myopathy and novel compound heterozygous mutations in the nebulin gene. 査読国際誌

Keiichiro Tsunoda, Toru Yamashita, Emi Motokura, Yoshiaki Takahashi, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Atsuko Nishikawa, Ichizo Nishino, Koji Abe

Journal of the neurological sciences 373 254 - 257 2017年2月

Potential multisystem degeneration in Asidan patients. 査読国際誌

Yasuyuki Ohta, Toru Yamashita, Nozomi Hishikawa, Kota Sato, Kosuke Matsuzono, Keiichiro Tsunoda, Noriko Hatanaka, Mami Takemoto, Toshihiko Takemi, Kazuhiro Takamatsu, Koji Abe

Journal of the neurological sciences 373 216 - 222 2017年2月

記述言語：英語掲載種別：研究論文（学術雑誌）

OBJECTIVE: To evaluate a potential multisystem involvement of neurodegeneration in Asidan, in addition to cerebellar ataxia and signs of motor neuron disease. METHODS: We compared the new Asidan patients and those identified in previous studies with Parkinson's disease (PD, n=21), and progressive supranuclear palsy (PSP, n=13) patients using 123I-2β-Carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) dopamine transporter single photon emission computed tomography (DAT-SPECT) and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy (Asidan, DAT: n=10; MIBG: n=15). RESULTS: Both the PD and PSP groups served as positive controls for DAT decline. The PD and PSP groups served as a positive and negative control, respectively, of MIBG decline in the early phase H/M ratio. Of the Asidan patients, 60.0% showed DAT decline without evident parkinsonian features and 6.7% showed impaired MIBG in only the delayed phase H/M ratio. Combined with a normal range of the early phase H/M ratio, this phenotype was newly named Declined DAT Without Evident Parkinsonism (DWEP). INTERPRETATION: The results of present study including DWEP suggest a wider spectrum of neurodegeneration for extrapyramidal and autonomic systems in Asidan patients than expected, involving cerebellar, motor system and cognitive functioning.

DOI： 10.1016/j.jns.2017.01.003

Marked hypertriglyceridemia induced by interferon-beta 1a therapy in a clinically isolated syndrome patient 査読国際誌

Yuko Kawahara, Toru Yamashita, Yasuyuki Ohta, Kota Sato, Keiichiro Tsunoda, Mami Takemoto, Nozomi Hishikawa, Jun Eguchi, Koji Abe

JOURNAL OF THE NEUROLOGICAL SCIENCES 373 144 - 146 2017年2月

A case of very long longitudinally extensive transverse myelitis (LETM) with necrotizing Vasculitis. 査読国際誌

Kota Sato, Keiichiro Tsunoda, Toru Yamashita, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Toshiyuki Takahashi, Ichiro Nakashima, Takao Yasuhara, Isao Date, Koji Abe

Journal of the neurological sciences 373 152 - 154 2017年2月

An AOA2 patient with a novel compound heterozygous SETX frame shift mutations. 査読国際誌

Emi Motokura, Toru Yamashita, Yoshiaki Takahashi, Keiichiro Tsunoda, Kota Sato, Mami Takemoto, Nozomi Hishikawa, Yasuyuki Ohta, Akihiro Hashiguchi, Hiroshi Takashima, Koji Abe

Journal of the neurological sciences 372 294 - 296 2017年1月

iPS cells and iN cells 査読

Toru Yamashita, Koji Abe

Cell Therapy against Cerebral Stroke: Comprehensive Reviews for Translational Researches and Clinical Trials 39 - 46 2017年1月

記述言語：英語掲載種別：論文集(書籍)内論文出版者・発行元：Springer Japan

The discovery of iPS indicated that overexpression of master transcriptional factors might change cell fate. Recent developments in reprogramming methods have shown that somatic cells can be directly reprogrammed to various kinds of neuronal cells directly. Moreover, overexpression of a neuron-specific transcriptional factor with a viral vector can change the fate of endogenous glial cells to neuronal cells in vivo. In this chapter, we discuss the advantages, issues, and possibility for clinical application of these reprogramming methods for cell transplantation/replacement therapy.

DOI： 10.1007/978-4-431-56059-3_4

Neuromyelitis Optica Spectrum Disorder Coinciding with Spinocerebellar Ataxia Type 31

Yoshiaki Takahashi, Yasuhiro Manabe, Ryuta Morihara, Hisashi Narai, Toru Yamashita, Koji Abe

CASE REPORTS IN NEUROLOGY 9 ( 2 ) 127 - 130 2017年

記述言語：英語掲載種別：研究論文（学術雑誌）出版者・発行元：KARGER

We report the unusual case of a 63-year-old man with spinocerebellar ataxia (SCA) type 31 who developed neuromyelitis optica spectrum disorder (NMOSD) 14 years after the onset of cerebellar symptoms. In addition to cerebellar atrophy, magnetic resonance imaging showed multiple high-intensity areas in the brain and a long thoracic cord lesion from Th1/2 to Th11. The combination of NMOSD and SCA31 is accidental. However, our case suggests that inflammatory processes could be involved in the pathogenesis of NMOSD and SCA31. (C) 2017 The Author(s) Published by S. Karger AG, Basel.

DOI： 10.1159/000475657

[Recent Progress in Cerebroprotective Therapy]. 査読

Toru Yamashita, Koji Abe

No shinkei geka. Neurological surgery 44 ( 12 ) 1001 - 1008 2016年12月

Sex-dependent effects of chromogranin B P413L allelic variant as disease modifier in amyotrophic lateral sclerosis. 査読国際誌

Yasuyuki Ohta, Genevieve Soucy, Daniel Phaneuf, Jean-Nicolas Audet, François Gros-Louis, Guy A Rouleau, Hélène Blasco, Philippe Corcia, Peter M Andersen, Frida Nordin, Toru Yamashita, Koji Abe, Jean-Pierre Julien

Human molecular genetics 25 ( 21 ) 4771 - 4786 2016年11月

記述言語：英語掲載種別：研究論文（学術雑誌）

Recent genetic studies yielded conflicting results regarding a role for the variant chromogranin B (CHGB)P413L allele as a disease modifier in ALS. Moreover, potential deleterious effects of the CHGBP413L variant in ALS pathology have not been investigated. Here we report that in transfected cultured cells, the variant CHGBL413 protein exhibited aberrant properties including mislocalization, failure to interact with mutant superoxide dismutase 1 (SOD1) and defective secretion. The CHGBL413 transgene in SOD1G37R mice precipitated disease onset and pathological changes related to misfolded SOD1 specifically in female mice. However, the CHGBL413 variant also slowed down disease progression in SOD1G37R mice, which is in line with a very slow disease progression that we report for a Swedish woman with ALS who is carrier of two mutant SOD1D90A alleles and two variant CHGBP413L and CHGBR458Q alleles. In contrast, overexpression of the common CHGBP413 allele in SOD1G37R mice did not affect disease onset but significantly accelerated disease progression and pathological changes. As in transgenic mice, the CHGBP413L allele conferred an earlier ALS disease onset in women of Japanese and French Canadian origins with less effect in men. Evidence is presented that the sex-dependent effects of CHGBL413 allelic variant in ALS may arise from enhanced neuronal expression of CHGB in females because of a sex-determining region Y element in the gene promoter. Thus, our results suggest that CHGB variants may act as modifiers of onset and progression in some ALS populations and especially in females because of higher expression levels compared to males.

DOI： 10.1093/hmg/ddw304

　前のページ - 次のページ　

1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17