Researchers Database

akimoto chizuru

    Centerforneurologyandneurosurgery,InternalMedicine Assistant Professor
Last Updated :2021/12/07

Researcher Information

J-Global ID

Published Papers

  • Chizuru Akimoto, Alexander E. Volk, Marka van Blitterswijk, Marleen Van den Broeck, Claire S. Leblond, Serge Lumbroso, William Camu, Birgit Neitzel, Osamu Onodera, Wouter van Rheenen, Susana Pinto, Markus Weber, Bradley Smith, Melanie Proven, Kevin Talbot, Pamela Keagle, Alessandra Chesi, Antonia Ratti, Julie van der Zee, Helena Alstermark, Anna Birve, Daniela Calini, Angelica Nordin, Daniela C. Tradowsky, Walter Just, Hussein Daoud, Sabrina Angerbauer, Mariely DeJesus-Hernandez, Takuya Konno, Anjali Lloyd-Jani, Mamede de Carvalho, Kevin Mouzat, John E. Landers, Jan H. Veldink, Vincenzo Silani, Aaron D. Gitler, Christopher E. Shaw, Guy A. Rouleau, Leonard H. van den Berg, Christine Van Broeckhoven, Rosa Rademakers, Peter M. Andersen, Christian Kubisch
    JOURNAL OF MEDICAL GENETICS 51 (6) 419 - 424 0022-2593 2014/06 [Refereed][Not invited]
     
    Background The GGGGCC-repeat expansion in C9orf72 is the most frequent mutation found in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Most of the studies on C9orf72 have relied on repeat-primed PCR (RP-PCR) methods for detection of the expansions. To investigate the inherent limitations of this technique, we compared methods and results of 14 laboratories. Methods The 14 laboratories genotyped DNA from 78 individuals (diagnosed with ALS or FTD) in a blinded fashion. Eleven laboratories used a combination of amplicon-length analysis and RP-PCR, whereas three laboratories used RP-PCR alone; Southern blotting techniques were used as a reference. Results Using PCR-based techniques, 5 of the 14 laboratories got results in full accordance with the Southern blotting results. Only 50 of the 78 DNA samples got the same genotype result in all 14 laboratories. There was a high degree of false positive and false negative results, and at least one sample could not be genotyped at all in 9 of the 14 laboratories. The mean sensitivity of a combination of amplicon-length analysis and RP-PCR was 95.0% (73.9-100%), and the mean specificity was 98.0% (87.5-100%). Overall, a sensitivity and specificity of more than 95% was observed in only seven laboratories. Conclusions Because of the wide range seen in genotyping results, we recommend using a combination of amplicon-length analysis and RP-PCR as a minimum in a research setting. We propose that Southern blotting techniques should be the gold standard, and be made obligatory in a clinical diagnostic setting.
  • Judith Eschbach, Birgit Schwalenstocker, Selma M. Soyal, Hanna Bayer, Diana Wiesner, Chizuru Akimoto, Ann-Charloth Nilsson, Anna Birve, Thomas Meyer, Luc Dupuis, Karin M. Danzer, Peter M. Andersen, Anke Witting, Albert C. Ludolph, Wolfgang Patsch, Patrick Weydt
    HUMAN MOLECULAR GENETICS 17 22 (17) 3477 - 3484 0964-6906 2013/09 [Refereed][Not invited]
     
    Amyotrophic lateral sclerosis (ALS) is a devastating, adult-onset neurodegenerative disorder of the upper and lower motor systems. It leads to paresis, muscle wasting and inevitably to death, typically within 35 years. However, disease onset and survival vary considerably ranging in extreme cases from a few months to several decades. The genetic and environmental factors underlying this variability are of great interest as potential therapeutic targets. In ALS, men are affected more often and have an earlier age of onset than women. This gender difference is recapitulated in transgenic rodent models, but no underlying mechanism has been elucidated. Here we report that SNPs in the brain-specific promoter region of the transcriptional co-activator PGC-1, a master regulator of metabolism, modulate age of onset and survival in two large and independent ALS populations and this occurs in a strictly male-specific manner. In complementary animal studies, we show that deficiency of full-length (FL) Pgc-1 leads to a significantly earlier age of onset and a borderline shortened survival in male, but not in female ALS-transgenic mice. In the animal model, FL Pgc-1-loss is associated with reduced mRNA levels of the trophic factor Vegf-A in males, but not in females. In summary, we indentify PGC-1 as a novel and clinically relevant disease modifier of human and experimental ALS and report a sex-dependent effect of PGC-1 in this neurodegenerative disorder.
  • Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, Hübers A, Keagle PJ, Piotrowska K, Press R, Andersen PM, Ludolph AC, Weishaupt JH
    Neurobiology of aging 6 34 1708.e1 - 6 0197-4580 2013/06 [Refereed][Not invited]
  • Akimoto C, Sakashita E, Kasashima K, Kuroiwa K, Tominaga K, Hamamoto T, Endo H
    Biochimica et biophysica acta 3 1830 (3) 2728 - 2738 0006-3002 2013/03 [Refereed][Not invited]
     
    BACKGROUND: Upstream open reading frames (uORFs) are commonly found in the 5'-untranslated region (UTR) of many genes and function in translational control. However, little is known about the existence of the proteins encoded by uORFs, and the role of the proteins except translational control. There was no report about uORFs of the McKusick-Kaufman syndrome (MKKS) gene that causes a genetic disorder. METHODS: Northern blotting, 3'-RACE, and bioinformatics were used for determining the length of transcripts and their 3' ends. Luciferase assay and in vitro translation were used for evaluation of translational regulatory activity of uORFs. Immunoblotting and immunocytochemical analyses were used for detection of uORF-derived protein products and their subcellular localization. RESULTS: The MKKS gene generates two types of transcripts: a canonical long transcript that encodes both uORFs and MKKS, and a short transcript that encodes only uORFs by using alternative polyadenylation sites at the 5'-UTR. The simultaneous disruption of the uORF initiation codons increased the translation of the downstream ORF. Furthermore, both protein products from the two longest uORFs were detected in the mitochondrial membrane fraction of HeLa cells. Database searches indicated that such uORFs with active alternative polyadenylation sites at the 5'-UTR are atypical but surely exist in human transcripts. CONCLUSIONS: Multiple uORFs at the 5'-UTR of the MKKS long transcript function as translational repressor for MKKS. Two uORFs are translated in vivo and imported onto the mitochondrial membrane. GENERAL SIGNIFICANCE: Our findings provide unique insights into production of uORF-derived peptides and functions of uORFs.
  • Chizuru Akimoto, Lars Forsgren, Jan Linder, Anna Birve, Irene Backlund, Jorgen Andersson, Ann-Charloth Nilsson, Helena Alstermark, Peter M. Andersen
    AMYOTROPHIC LATERAL SCLEROSIS AND FRONTOTEMPORAL DEGENERATION 14 (1) 26 - 29 2167-8421 2013/01 [Refereed][Not invited]
     
    An intronic GGGGCC-hexanucleotide repeat expansion in C9ORF72 was recently identified as a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. Some amyotrophic lateral sclerosis patients have signs of parkinsonism, and many parkinsonism patients develop dementia. In this study we examined if the hexanucleotide repeat expansion was present in parkinsonism patients, to clarify if there could be a relationship between the repeat expansion and disease. We studied the size of the hexanucleotide repeat expansion in a well defined population-based cohort of 135 Parkinson's disease patients and 39 patients with atypical parkinsonism and compared with 645 Swedish control subjects. We found no correlation between Parkinson's disease or atypical parkinsonism and the size of the GGGGCC repeat expansion in C9ORF72. In conclusion, this GGGGCC-repeat expansion in C9ORF72 is not a cause of parkinsonism in the Swedish population.
  • Aritoshi Iida, Atsushi Takahashi, Min Deng, Yun Zhang, Jing Wang, Naoki Atsuta, Fumiaki Tanaka, Tetsumasa Kamei, Motoki Sano, Shuichi Oshima, Torao Tokuda, Mitsuya Morita, Chizuru Akimoto, Masahiro Nakajima, Michiaki Kubo, Naoyuki Kamatani, Imaharu Nakano, Gen Sobue, Yusuke Nakamura, Dongsheng Fan, Shiro Ikegawa
    NEUROBIOLOGY OF AGING 32 (4) 757.e13 - 4 0197-4580 2011/04 [Refereed][Not invited]
     
    We performed a replication study of the 2 genetic variants, rs2814707 on 9p21.2 and rs12608932 on 19p13.3 that are recently reported to be most significantly associated with sporadic amyotrophic lateral sclerosis (ALS) in Caucasians. Both rs12608932 and rs2814707 showed no evidence of association in Japanese and Chinese (rs12608932, combined p = 0.58, odds ratio [OR] = 1.03, 95% confidence interval [CI] 0.93-1.13; rs2814707, combined p = 0.88, OR = 1.10, 95% CI 0.93-1.30). The association of these loci with susceptibility to sporadic ALS is considered negative in East Asians. (C) 2011 Elsevier Inc. All rights reserved.
  • Chizuru Akimoto, Mitsuya Morita, Naoki Atsuta, Gen Sobue, Imaharu Nakano
    Neurology research international 2011 165415 - 165415 2090-1852 2011 [Refereed][Not invited]
     
    Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, and the majority of ALS are sporadic (SALS). Recently, several causative genes for familial ALS (FALS) were identified, but the cause of the SALS is still unknown. This time, we aimed to identify the genetic background of SALS. First, we applied the new sensitive screening methods: high-resolution melting (HRM) analysis. HRM analysis detected 18 out of 19 known SOD1 gene mutations (94.7% sensitivity). Next, we screened SOD1, three novel mutations (C6Y, Q22H, and S134T) were identified in our own 184 SALS cases (1.63% prevalence), and four mutations in another 255 SALS cases (1.56% prevalence) registered from all over Japan. The patients with SOD1 mutations suggested a relatively young onset and limb involvement at onset. The HRM analysis is a sensitive and easy screening method; we will use this method for screening other ALS causative genes and revealing the genetic background of SALS.
  • Chizuru Akimoto, Mitsuya Morita, Masahiko Yamamoto, Imaharu Nakano
    Clinical Neurology 50 (6) 399 - 403 0009-918X 2010 [Refereed][Not invited]
     
    CMTX1, the second most common type of inherited hereditary motor and sensory neuropathy (HMSN), is associated with mutations of the gene for the gap junction protein connexin 32 (Cx32). In this condition, central conduction velocity is known to be delayed, presumably because mutated Cx32 is expressed in oligodendrocytes. A 45-year-old man presented with a 5-year history of progressive gait disturbance due to leg muscle weakness. The family history revealed that the mother had also progressive gait disturbance in her early 40s, and the younger sister could not walk faster than before at the age of 41. On neurological assessment the patient exhibited pes cavus, distal muscle atrophy and weakness, and absence of the knee and ankle jerks. Touch sensation was impaired in the both feet Motor and sensory nerve conduction velocities were reduced to 30-36 m/s with mild temporal dispersion. Sural nerve biopsy revealed diffuse loss of large myelinated fibers with the remaining large and intermediate nerve fibers being frequently surrounded by a thin myelin sheath. Onion bulb formation was only occasional and mild in degree. His hearing acuity was normal on pure-tone audiometry, but BAEP test demonstrated prolonged central conduction time (-I wave 1.8 milliseconds, I-V wave 6.4 milliseconds). The BAEP findings prompted us to choose Cx32 gene to analyze first to find a novel mutation of two (A and T) base pairs deletion at codons 277 and 278 (Met93fs). Thus, the present case indicates that Cx32 gene mutation should be targeted first in case of HMSN with abnormal BAEP.
  • Chizuru Kawamata, Mitsuya Morita, Noriyuki Shibata, Imaharu Nakano
    Clinical Neurology 47 (5) 211 - 216 0009-918X 2007/05 [Refereed][Not invited]
     
    We describe a patient with familial amyotrophic lateral sclerosis (FALS) in whom we identified a substitution of G for CGTTTA at codon 144 in the Cu/Zn superoxide dismutase 1 (SOD1) gene, causing amino acid changes from leucine to phenylalanine, valine and a stop codon (L144FVX). This mutation is novel, and so we report the clinical and neuropathological features of this case compared with those of other FALS cases with SOD1 mutations. A 39-year-old woman developed muscle weakness and atrophy in the hands, which rapidly progressed and expanded to other muscles, resulting in respiratory insufficiency and death at only 10 months after the onset. Her grandmother, father and uncle had also been diagnosed as having ALS. The most noticeable neuropathological findings in the present case were marked loss of large motor neurons in the anterior horns associated with the frequent appearance of cord-like swollen, partially SOD1- and ubiquitin-immunopositive axons. These findings together with the absence of Bunina bodies are compatible with the neuropathology of FALS with SOD1 gene mutation, although Lewy body-like inclusions characteristic for this condition were not observed.


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