Takeshi Amino

Musashino Red Cross Hospital, Edo, Tōkyō, Japan

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Publications (27)89.48 Total impact

  • Neurological Sciences 08/2014; 36(5). DOI:10.1007/s10072-014-1916-0 · 1.45 Impact Factor
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    ABSTRACT: Serum amyloid A (SAA) is known to promote the development of T helper 17 cells (Th17) and can be a critical mediator of disease pathogenesis. We analyzed SAA levels in 40 patients with multiple sclerosis (MS) and related disorders, and 10 with non-inflammatory neurological disease (NIND) as controls. We found that SAA levels were significantly increased in neuromyelitis optica (NMO) patients and relapsing and remitting MS (RRMS) patients showing atypical phenotype with spinal cord lesions and smaller T2 lesion volume in brain MRI, resembling NMO. Therefore, SAA levels can be associated with clinical phenotypes in MS and NMO.
    Journal of neuroimmunology 04/2013; 259(1). DOI:10.1016/j.jneuroim.2013.03.004 · 2.47 Impact Factor
  • Acta neurologica Belgica 10/2012; 113(3). DOI:10.1007/s13760-012-0143-9 · 0.89 Impact Factor
  • Neurological Sciences 07/2012; 34(6). DOI:10.1007/s10072-012-1171-1 · 1.45 Impact Factor
  • Acta neurologica Belgica 07/2012; 113(2). DOI:10.1007/s13760-012-0118-x · 0.89 Impact Factor
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    ABSTRACT: We present here the rare case of a 73-year-old patient with very late-onset multiple sclerosis who developed autoimmune polyendocrine syndrome (APS)-3. Despite only a few reports describing the association between multiple sclerosis and APS, both of these diseases have been shown to be associated with HLA-DR4. Intriguingly, the HLA genotype profile of this patient included HLA-DR4 which, fine mapped to the DRB1*0405-DQA1*0303-DQB1*0401 extended haplotype, reported to be a susceptibility haplotype for APS-3 in Japan. This unique genetic background might explain the clinical picture of this patient.
    The Neurologist 03/2012; 18(2):83-4. DOI:10.1097/NRL.0b013e318248ea2a · 1.16 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia type 31 (SCA31) was recently discovered to be caused by 2.5- to 3.8-kb-long complex pentanucleotide repeats containing (TGGAA)(n), (TAGAA)(n), and (TAAAA)(n) in an intronic region shared by 2 different genes, BEAN (brain expressed, associated with Nedd4) and TK2 (thymidine kinase 2), in chromosome 16q22.1.(1,2) Among the 3 pentanucleotide repeats, (TGGAA)(n) was the only one in which large repeats segregated with the phenotype, suggesting its importance in pathogenesis.(2) SCA31 is considered one of a growing number of neuromuscular diseases with RNA-mediated gain-of-function mechanism such as myotonic dystrophies type 1 and 2, SCA8, SCA10, and fragile X-tremor ataxia syndrome.(3).
    Neurology 11/2011; 77(20):1853-5. DOI:10.1212/WNL.0b013e3182377e3a · 8.29 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia is a group of neurodegenerative disorders clinically presenting adult onset cerebellar ataxia. To date, 21 different genes (SCA1, 2, 3, 5, 6, 7, 8, 10, 11, 12, 13, 14, 15, 17, 23, 27, 28, 31, 35, 36 and DRPLA) and additionally 10 different gene loci (SCA4, 18, 19, 20, 21, 25, 26, 29, 30 and 32) are identified. Among these, SCA6 and SCA31 are the two common diseases clinically presenting as a relatively predominant cerebellar syndrome, whereas Machado-Joseph disease/SCA3, DRPLA, SCA1 and SCA2 are SCAs often associated with extra-cerebellar manifestations. SCA31 is a late-onset purely cerebellar ataxia caused by a complex pentanucleotide repeat containing (TGGAA)(n) lying in an intronic region shared by two genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2). In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"), and essential splicing factors, SFRS1 and SFRS9, bind to (UGGAA)(n), the transcript of (TGGAA)(n)in vitro. Our preliminary data also demonstrated that (UGGAA)(n) is toxic when expressed in cultured cells. These findings may imply that RNA-mediated pathogenesis is involved in SCA31. Further studies are needed to explore precise mechanism of this disease.
    11/2011; 51(11):1122-4. DOI:10.5692/clinicalneurol.51.1122
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    ABSTRACT: Spinocerebellar ataxia type 31 (SCA31) is a relatively common degenerative ataxia in Japan. We recently discovered SCA31 mutation as a complex pentanucleotide repeat containing (TAAAA)(n), (TAGAA)(n), and (TGGAA)(n). The size of this repeat ranged from 2.8 to 3.5 kilo-base pairs (kb). Among these repeats, (TGGAA)(n) repeat appears crucial for SCA31 pathogenesis. The length of this complex repeat inversely correlated with ages of onset in patients. The mutation lies in an intron shared by two different genes, BEAN (brain expressed, associated with NEDD4) and TK2 (thymidine kinase 2), which are transcribed in opposite directions. Thus, the complex pentanucleotide sequence is predicted to be transcribed in both directions, but not necessarily translated into proteins. In situ hybridization analysis in patients' Purkinje cells demonstrated that pentanucleotide repeats transcribed in BEAN direction form RNA aggregates ("RNA foci"). We further found that splicing factors, SFRS1 and SFRS9, binds to (UGGAA)(n), the transcript of (TGGAA)(n) in vitro. These findings may imply that SCA31 conforms to pathogenic mechanisms underlying non-coding repeat disorders, such as myotonic dystrophies (DM1 & DM2), and that SFRS1 and SFRS9 are involved in SCA31 pathogenesis.
    11/2010; 50(11):985-7. DOI:10.5692/clinicalneurol.50.985
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    ABSTRACT: Spinocerebellar ataxia type 6 (SCA6) is an autosomal dominant neurodegenerative disease caused by a small polyglutamine (polyQ) expansion (control: 4-20Q; SCA6: 20-33Q) in the carboxyl(C)-terminal cytoplasmic domain of the alpha(1A) voltage-dependent calcium channel (Ca(v)2.1). Although a 75-85-kDa Ca(v)2.1 C-terminal fragment (CTF) is toxic in cultured cells, its existence in human brains and its role in SCA6 pathogenesis remains unknown. Here, we investigated whether the small polyQ expansion alters the expression pattern and intracellular distribution of Ca(v)2.1 in human SCA6 brains. New antibodies against the Ca(v)2.1 C-terminus were used in immunoblotting and immunohistochemistry. In the cerebella of six control individuals, the CTF was detected in sucrose- and SDS-soluble cytosolic fractions; in the cerebella of two SCA6 patients, it was additionally detected in SDS-insoluble cytosolic and sucrose-soluble nuclear fractions. In contrast, however, the CTF was not detected either in the nuclear fraction or in the SDS-insoluble cytosolic fraction of SCA6 extracerebellar tissues, indicating that the CTF being insoluble in the cytoplasm or mislocalized to the nucleus only in the SCA6 cerebellum. Immunohistochemistry revealed abundant aggregates in cell bodies and dendrites of SCA6 Purkinje cells (seven patients) but not in controls (n = 6). Recombinant CTF with a small polyQ expansion (rCTF-Q28) aggregated in cultured PC12 cells, but neither rCTF-Q13 (normal-length polyQ) nor full-length Ca(v)2.1 with Q28 did. We conclude that SCA6 pathogenesis may be associated with the CTF, normally found in the cytoplasm, being aggregated in the cytoplasm and additionally distributed in the nucleus.
    Acta Neuropathologica 04/2010; 119(4):447-64. DOI:10.1007/s00401-009-0630-0 · 10.76 Impact Factor
  • Neuroscience Research 12/2009; 65. DOI:10.1016/j.neures.2009.09.1691 · 1.94 Impact Factor
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    ABSTRACT: Spinocerebellar ataxia (SCA) is a group of degenerative ataxias with autosomal dominant inheritance. The most common form of mutation that causes SCA is the expansion of trinucleotide (CAG) repeat encoding polyglutamine. These "polyglutamine disorders" are, SCA1, SCA2, Machado-Joseph disease, SCA6, SCA7, SCA17 and DRPLA. Another dynamic mutation, yet a non-coding one, has been identified as the cause of SCA8, SCA10 and SCA12. This mutation includes, trinucleotide (CAG/CTG) expansion causing SCA8 and SCA12, and pentanuclotide (ATTCT) expansion leading SCA10. In addition to these dynamic mutations, static mutations, such as missense mutations and deletions, have been identified to cause SCA5, SCA11, SCA13, SCA14, SCA15 and SCA27. Since 1992, authors have been involved in identifying the mutation (s) of autosomal dominant cerebellar ataxia with rather pure cerebellar syndrome (ADCAIII). About a half of our cohort with ADCAIII were SCA6, caused by a small CAG repeat expansion in the alpha1A-voltage-dependent calcium channel gene. Recent study in patients' brains suggested that a small polyglutamine expansion leads a portion of this channel protein to aggregate in the Purkinje cell. Another type of ADCAIII is the chromosome 16q22.1-linked ADCA. By a comprehensive positional cloning strategy, we have found a genetic change that segregate with the disease. Identifying the mutation of 16q-ADCA is imperative for understanding molecular basis of this disease.
    Rinsho shinkeigaku = Clinical neurology 11/2009; 49(11):907-9. DOI:10.5692/clinicalneurol.49.907
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    ABSTRACT: Spinocerebellar ataxia type 31 (SCA31) is an adult-onset autosomal-dominant neurodegenerative disorder showing progressive cerebellar ataxia mainly affecting Purkinje cells. The SCA31 critical region was tracked down to a 900 kb interval in chromosome 16q22.1, where the disease shows a strong founder effect. By performing comprehensive Southern blot analysis and BAC- and fosmid-based sequencing, we isolated two genetic changes segregating with SCA31. One was a single-nucleotide change in an intron of the thymidine kinase 2 gene (TK2). However, this did not appear to affect splicing or expression patterns. The other was an insertion, from 2.5-3.8 kb long, consisting of complex penta-nucleotide repeats including a long (TGGAA)n stretch. In controls, shorter (1.5-2.0 kb) insertions lacking (TGGAA)n were found only rarely. The SCA31 repeat insertion's length inversely correlated with patient age of onset, and an expansion was documented in a single family showing anticipation. The repeat insertion was located in introns of TK2 and BEAN (brain expressed, associated with Nedd4) expressed in the brain and formed RNA foci in the nuclei of patients' Purkinje cells. An electrophoretic mobility-shift assay showed that essential splicing factors, serine/arginine-rich splicing factors SFRS1 and SFRS9, bind to (UGGAA)n in vitro. Because (TGGAA)n is a characteristic sequence of paracentromeric heterochromatin, we speculate that the insertion might have originated from heterochromatin. SCA31 is important because it exemplifies human diseases associated with "inserted" microsatellite repeats that can expand through transmission. Our finding suggests that the ectopic microsatellite repeat, when transcribed, might cause a disease involving the essential splicing factors.
    The American Journal of Human Genetics 10/2009; 85(5):544-57. DOI:10.1016/j.ajhg.2009.09.019 · 10.93 Impact Factor
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    ABSTRACT: Recently, we reported a profound depletion of cardiac sympathetic nerve fibers in Parkinson's disease (PD). This cardiac sympathetic denervation is a characteristic hallmark of PD. Cardiac sympathetic dysfunction was also observed in 1-methyl-4-phenyl-1,2,3,6-tetrahydroxypyridine (MPTP)-treated mice, a model of PD. Although binding assay showed a decreased density of norepinephrine transporter (NET) in the hearts of the mice, their histopathological alterations have not been demonstrated. In this study, we investigated hearts of MPTP-treated mice with immunohistochemical method and Western blot analyses. MPTP-treated mice showed significant decreases in the contents of cardiac noradrenaline and dopamine, suggesting the sympathetic dysfunction. Synaptophysin-, tyrosine hydroxylase- or NET-immunoreactive nerve fibers were abundant in the hearts of control mice and MPTP-treated mice, without apparent differences between the two groups. Western blot analyses also showed no difference in the amounts of these proteins. Myocardial nerve fibers were well preserved in MPTP-treated mice, despite apparent cardiac sympathetic dysfunction.
    Neuroscience Research 04/2008; 60(3):314-8. DOI:10.1016/j.neures.2007.11.011 · 1.94 Impact Factor
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    ABSTRACT: Multiple system atrophy (MSA) is a sporadic neurodegenerative disease manifested clinically by progressive ataxia, parkinsonism, and autonomic dysfunction. Its cause is unknown, and there is no curative therapy. Alpha-synuclein is an important protein forming aggregations called glial cytoplasmic inclusions (GCIs) in oligodendroglia; these aggregations are considered important in MSA pathogenesis. Overexpression of the human alpha-synuclein gene in mice induces the formation of GCI-like aggregations in oligodendrocytes, leading mice to exhibit neurological signs similar to those in MSA patients. However, previous studies have excluded mutations within the coding region of the alpha-synuclein gene in MSA patients. To determine whether alteration in the expression level of the alpha-synuclein gene is associated with MSA pathogenesis, we used TaqMan quantitative PCR assay to analyze the alpha-synuclein gene copy number in patients' genomes. We also used quantitative RT-PCR and in situ hybridization to analyze alpha-synuclein mRNA expression in MSA patients' brain tissues. We found no alteration in the alpha-synuclein gene copy number in the patients' genomes (n = 50). Quantitative analysis for alpha-synuclein mRNA by the TaqMan method showed that alpha-synuclein mRNA levels were comparable between control (n = 3) and MSA (n = 3) cerebella. On in situ hybridization, the number of neurons with alpha-synuclein mRNA expression was no greater in the cerebella of MSA patients (n = 3) than in the controls (n = 3). However, GCIs were seen in these MSA specimens on immunohistochemistry for alpha-synuclein. These results suggest that alpha-synuclein gene expression is not the fundamental cause of MSA.
    Journal of medical and dental sciences 03/2008; 55(1):145-53.
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    ABSTRACT: Spinocerebellar ataxia type 1 (SCA1; OMIM: #164400) is an autosomal dominant cerebellar ataxia caused by an expansion of CAG repeat, which encodes polyglutamine, in the ataxin-1 (ATXN1) gene. Length of polyglutamine in the ATXN1 protein is the critical determinant of pathogenesis of this disease. Molecular diagnosis of SCA1 is usually undertaken by assessing the length of CAG repeat configuration using primers spanning this configuration. However, this conventional method may potentially lead to misdiagnosis in assessing polyglutamine-encoding CAG repeat length, since CAT interruptions may be present within the CAG repeat configuration, not only in normal controls but also in neurologically symptomatic subjects. We developed a new method for assessing actual CAG repeat numbers not interrupted by CAT sequences. Polymerase chain reaction using a primer pair labeled with two different fluorescences followed by restriction enzyme digestion with SfaNI which recognizes the sequence "GCATC(N)(5)", lengths of actual CAG repeats that encode polyglutamine were directly detected. We named this method "dual fluorescence labeled PCR-restriction fragment length analysis". We found that numbers of actual CAG repeat encoding polyglutamine do not overlap between our cohorts of normal chromosomes (n=385) and SCA1 chromosomes (n=5). We conclude that the present method is a useful way for molecular diagnosis of SCA1.
    Journal of Human Genetics 02/2008; 53(4):287-95. DOI:10.1007/s10038-007-0242-2 · 2.46 Impact Factor
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    ABSTRACT: Decreased cardiac uptake of meta-iodobenzylguanidine (MIBG) has been reported in patients with Parkinson's disease (PD), dementia with Lewy bodies (DLB) and pure autonomic failure (PAF). This imaging approach is a sensitive diagnostic tool that possibly differentiates PD and DLB from other movement disorders and Alzheimer's disease (AD). We recently reported cardiac sympathetic denervation in PD, DLB and PAF, which accounts for the decreased cardiac uptake of MIBG in these disorders. Patients with PD, DLB and PAF have Lewy bodies (LBs) in the nervous system, whereas patients with multiple system atrophy (MSA), progressive supranuclear palsy, corticobasal degeneration, AD and parkin-associated PD have no LBs in the nervous system. Even in patients with MSA, cardiac sympathetic denervation was associated with the presence of LBs. Therefore, cardiac sympathetic denervation is closely related to the presence of LBs in a wide range of neurodegenerative processes. Taken together, we conclude that the decreased cardiac uptake of MIBG is a potential biomarker for the presence of LBs.We infer that MIBG myocardial scintigraphy is a non-invasive tool that allows us to detect LBs during life.
    Journal of Neurology 08/2007; 254:IV21-IV28. DOI:10.1007/s00415-007-4005-y · 3.38 Impact Factor
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    ABSTRACT: The 16q22.1-linked autosomal dominant cerebellar ataxia (16q-ADCA; Online Mendelian Inheritance in Man [OMIN] #117210) is one of the most common ADCAs in Japan. Previously, we had reported that the patients share a common haplotype by founder effect and that a C-to-T substitution (-16C>T) in the puratrophin-1 gene was strongly associated with the disease. However, recently, an exceptional patient without the substitution was reported, indicating that a true pathogenic mutation might be present elsewhere. In this study, we clarified the disease locus more definitely by the haplotype analysis of families showing pure cerebellar ataxia. In addition to microsatellite markers, the single nucleotide polymorphisms (SNPs) that we identified on the disease chromosome were examined to confirm the borders of the disease locus. The analysis of 64 families with the -16C>T substitution in the puratrophin-1 gene revealed one family showing an ancestral recombination event between SNP04 and SNP05 on the disease chromosome. The analysis of 22 families without identifiable genetic mutations revealed another family carrying the common haplotype centromeric to the puratrophin-1 gene, but lacking the -16C>T substitution in this gene. We concluded that the disease locus of 16q-ADCA was definitely confined to a 900-kb genomic region between the SNP04 and the -16C>T substitution in the puratrophin-1 gene in 16q22.1.
    Journal of Human Genetics 07/2007; 52(8):643-9. DOI:10.1007/s10038-007-0154-1 · 2.46 Impact Factor
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    ABSTRACT: The autosomal dominant cerebellar ataxias (ADCAs) comprise a genetically and clinically heterogenous group of neurodegenerative disorders. Very recently, a C-to-T single nucleotide substitution in the puratrophin-1 gene was found to be strongly associated with a form of ADCA linked to chromosome 16q22.1 (16q-linked ADCA; OMIM 600223). We found the C-to-T substitution in the puratrophin-1 gene in 20 patients with ataxia (16 heterozygotes and four homozygotes) and four asymptomatic carriers in 9 of 24 families with an unknown type of ADCA. We also found two cases with 16q-linked ADCA among 43 sporadic patients with late-onset cortical cerebellar atrophy (LCCA). The mean age at onset in the 22 patients was 61.8 years, and that of homozygous patients was lower than that of heterozygous ones in one family. Neurological examination revealed that the majority of our patients showed exaggerated deep tendon reflexes in addition to the cardinal symptom of cerebellar ataxia (100%), and 37.5% of them had sensorineural hearing impairment, whereas sensory axonal neuropathy was absent. The frequency of 16q-linked ADCA was about 1/10 of our series of 110 ADCA families, making it the third most frequent ADCA in Japan.
    Journal of the Neurological Sciences 10/2006; 247(2):180-6. DOI:10.1016/j.jns.2006.04.009 · 2.47 Impact Factor
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    ABSTRACT: [123I]meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is a useful diagnostic tool to differentiate Parkinson's disease and dementia with Lewy bodies (Lewy body disease) from other related movement disorders, PARK2, and Alzheimer's disease. Postmortem study revealed that cardiac sympathetic denervation occurs in Lewy body disease and indicates the presence of Lewy pathology, which accounts for the decreased cardiac uptake of MIBG in Lewy body disease. Moreover, degeneration of cardiac sympathetic nerve precedes the neuronal loss in the sympathetic ganglia.
    Parkinsonism & Related Disorders 10/2006; 12. DOI:10.1016/j.parkreldis.2006.05.030 · 3.97 Impact Factor

Publication Stats

583 Citations
89.48 Total Impact Points


  • 2012–2014
    • Musashino Red Cross Hospital
      Edo, Tōkyō, Japan
  • 2005–2011
    • Tokyo Medical and Dental University
      • Department of Neurology and Neurological Science
      Tokyo, Tokyo-to, Japan
  • 2008
    • Tokyo Metropolitan Institute
      Edo, Tōkyō, Japan
  • 2004–2005
    • Kanto Central Hospital
      Edo, Tōkyō, Japan