Increase of disease duration of amyotrophic lateral sclerosis in a mouse model by transgenic small interfering RNA.
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Amyotrophic Lateral Sclerosis↗
Biomedical subjects
Hidehiro Mizusawa
Publications and source records attributed to Hidehiro Mizusawa.
Geographic difference of mortality of Creutzfeldt-Jakob disease in Japan.
BACKGROUND: The geographic mortality difference of Creutzfeldt-Jakob disease is still unclear in Japan. METHODS: Using vital statistics of Japan for 6 year period between 1999 and 2004 officially published by the government, we observed the mortality from Creutzfeldt-Jakob disease (ICD-10th: A81.0 and A81.8) by prefecture. Standardized mortality ratios were calculated for the 47 prefectures. RESULTS: For the observed 6 years, a total of 792 deaths from Creutzfeldt-Jakob disease were observed whole in Japan. Two prefectures, Akita and Yamanashi, presented significantly high standardized mortality ratios. In addition, Tochigi, Kochi, and Nagasaki showed standardized mortality rates higher than 1.5 without significance. No prefecture had significantly low standardized mortality ratios. CONCLUSION: Some prefectures with high mortality rate from Creutzfeldt-Jakob disease existed in Japan. Some of them had high incidence rate in a survey conducted in 1996 as well.
Adolescent↗
[Roundtable discussion: advances in neuroscience and therapeutic research on neurological diseases--the present status and future prospects].
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Biomedical Research↗
Cerebral networks for spontaneous and synchronized singing and speaking.
Singing in unison is usually easier than singing alone, but the neural mechanism underlying these two contrasting modes of singing remains unknown. We investigated neural correlates of singing by a functional magnetic resonance imaging study focusing on the capacities of spontaneity and synchronization and compared them with those of speaking. The left inferior frontal gyrus appears important for self-generation of text in singing and speaking without auditory input, whereas the left posterior planum temporale plays a key role in synchronizing both text and melody, in combination with the bilateral inferior parietal lobule for singing along, and with the left angular gyrus for speaking in chorus. These findings indicate that text and melody are not processed symmetrically or parallel in singing a well-learned song.
Adult↗
A case of Listeria meningitis associated with increased adenosine deaminase in cerebrospinal fluid.
We present, to the best of our knowledge, the first case of listeria meningitis with increased adenosine deaminase (ADA) in cerebrospinal fluid. Although some cases of other etiologies were also reported, this report informs those who manage patients with meningitis that not only Mycobacterium and Brucella spp. but also other facultative agents can increase ADA levels in cerebrospinal fluid, possibly through monocyte-macrophage activation.
Adenosine Deaminase↗
Selective loss of Purkinje cells in a patient with anti-glutamic acid decarboxylase antibody-associated cerebellar ataxia.
Anti-glutamic acid decarboxylase antibody is associated with the development of progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus. Previously, the neurophysiological characteristics of IgG in the cerebrospinal fluid of a patient with anti-glutamic acid decarboxylase antibody-associated progressive cerebellar ataxia and slowly progressive insulin-dependent diabetes mellitus were reported. Using a voltage-gated whole-cell recording technique, it was observed that the IgG in the cerebrospinal fluid of the patient selectively suppressed the inhibitory postsynaptic currents in the Purkinje cells. The patient died from aspiration pneumonia. Postmortem examination showed almost complete depletion of the Purkinje cells with Bergmann gliosis. Therefore, the main cause of cerebellar ataxia observed in this case may be attributed to the near-complete depletion of the Purkinje cells. In this paper, the pathomechanisms underlying Purkinje cell damage are discussed.
Aged↗
Deletion of vitamin E enhances phenotype of Alzheimer disease model mouse.
Increased oxidative damage is a prominent and early feature in Alzheimer disease (AD). However, whether it is a primary cause or merely a downstream consequence in AD pathology is still unknown. We previously generated alpha-tocopherol transfer protein knockout (Ttpa-/-) mice, in which lipid peroxidation in the brain was significantly increased by complete depletion of alpha-tocopherol (alpha-Toc). Here we crossed AD transgenic (APPsw) model mice (Tg2576) with Ttpa-/- mice. The resulting double-mutant (Ttpa-/- APPsw) mice showed earlier and more severe cognitive dysfunction in the Morris water maze, novel-object recognition, and contextual fear conditioning tests. They also showed increased amyloid beta-peptide (Abeta) deposits in the brain by immunohistochemical analysis, which was ameliorated with alpha-Toc supplementation. In this report we provide clear evidence indicating that chronic lipid peroxidation due to alpha-Toc depletion enhances AD phenotype in a mouse model.
Alzheimer Disease↗
A carbohydrate-binding protein, Galectin-1, promotes proliferation of adult neural stem cells.
In the subventricular zone of the adult mammalian forebrain, neural stem cells (NSCs) reside and proliferate to generate young neurons. We screened factors that promoted the proliferation of NSCs in vitro by a recently developed proteomics technique, the ProteinChip system. In this screen, we identified a soluble carbohydrate-binding protein, Galectin-1, as a candidate. We show herein that Galectin-1 is expressed in a subset of slowly dividing subventricular zone astrocytes, which includes the NSCs. Based on results from intraventricular infusion experiments and phenotypic analyses of knockout mice, we demonstrate that Galectin-1 is an endogenous factor that promotes the proliferation of NSCs in the adult brain.
Animals↗
A -16C>T substitution in the 5' UTR of the puratrophin-1 gene is prevalent in autosomal dominant cerebellar ataxia in Nagano.
The molecular bases of autosomal dominant cerebellar ataxia (ADCA) have been increasingly elucidated, but 17-50% of ADCA families still remain genetically undefined in Japan. In this study we investigated 67 genetically undefined ADCA families from the Nagano prefecture, and found that 63 patients from 51 families possessed the -16C>T change in the puratrophin-1 gene, which was recently found to be pathogenic for 16q22-linked ADCA. Most patients shared a common haplotype around the puratrophin-1 gene. All patients with the -16C>T change had pure cerebellar ataxia with middle-aged or later onset. Only one patient in a large, -16C>T positive family did not have this change, but still shared a narrowed haplotype with, and was clinically indistinguishable from, the other affected family members. In Nagano, 16q22-linked ADCA appears to be much more prevalent than either SCA6 or dentatorubral-pallidoluysian atrophy (DRPLA), and may explain the high frequency of spinocerebellar ataxia.
5' Untranslated Regions↗
Dynamic imbalance in gait ataxia. Characteristics of plantar pressure measurements.
The present study was designed to evaluate the interaction between disequilibrium and irregular stepping components of ataxic gait. For this purpose, we compared the walking patterns of patients with cerebellar dominant multiple system atrophy (MSAc, n = 8), spinocerebellar ataxia type 6 (SCA6, n = 4) and 16q-linked autosomal dominant cortical cerebellar atrophy (16q-linked ADCA, n = 6), and 6 normal subjects, by measuring toe and heel plantar pressures. In healthy subjects, the heel contacted the floor at step-in followed by an immediate shift of the center of pressure (COP) to the contacted leg. In ataxic gait, however, both the heel and toes simultaneously contacted the floor and the disappearance of the immediate shift of the COP was noted. These changes appeared to be nonspecific compensations for the instability. Examination of two parameters of ataxia-specific changes showed that prolongation of the double support period was associated with proportionate increase in the coefficients of variance of the plantar pressures and the step lengths on walking of patients with SCA6, but not those with MSAc and 16q-linked ADCA. Our results suggest that disequilibrium and irregularity are two separate and independent components of cerebellar ataxic gait.
Adult↗
Three-repeat Tau 69 is a major tau isoform in laser-microdissected Pick bodies.
By utilizing a novel combinatorial method of a Laser Microdissection System and Western blot analysis, we demonstrate that a distinct isoform of abnormally phosphorylated tau (69 kDa, Tau 69) predominantly aggregated in laser-microdissected Pick bodies (PBs) in sporadic Pick's disease. By contrast, tau migrated as two major bands of 60 and 64 kDa (Tau 60 and 64) in total brain homogenates as previously reported. Comparative immunohistochemical analysis with anti-4-repeat antibody revealed that a major component of the abnormally phosphorylated tau in these PBs was 3-repeat tau (3R-tau). Whether 29 amino acid repeat encoded by exons 2 and 3 in the Tau 69 might accelerate the formation of PBs remains to be further investigated. Such a combination of morphological and biochemical techniques significantly complements the existing histopathological methods.
Aged↗
Predominant motor symptoms in a 74-year-old man with a small elongation in the spinocerebellar atrophy type 1 gene.
The patient was a 74-year-old man who developed gait and bulbar disturbances, which progressed for several years. His mother and a sister complained of a similar disturbance. On admission, generalized muscle atrophy and weakness were prominent, especially in the distal portions of the legs, with bulbar involvement. The patellar tendon reflexes were retained and the Achilles tendon reflexes were decreased with a positive right Babinski's sign. The ocular movements were restricted in vertical directions and, to a lesser extent, in horizontal directions. Sensory disturbance, ataxia, and extrapyramidal signs were not apparent on admission. A needle electromyogram demonstrated neurogenic changes. The laboratory examination was normal except for elevated blood glucose (320 mg/dL) and creatine kinase (1760 U/L). His general condition deteriorated so rapidly that intractable respiratory distress due to pneumonia led to a fatal outcome. The clinical diagnosis was motor neuron disease, although a familial background and a disturbance in ocular movements might have suggested other possibilities.
Aged↗
On autosomal dominant cerebellar ataxia (ADCA) other than polyglutamine diseases, with special reference to chromosome 16q22.1-linked ADCA.
Autosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous conditions. More than 20 genes or gene loci have been identified that are responsible for ADCA. Although expansions of the trinucleotide (CAG) repeat that encode polyglutamine are known to cause some forms of ADCA, growing knowledge about the genetic basis of ADCA indicates that many subtypes of ADCA are caused by mutations other than the CAG repeat/polyglutamine expansion. In this paper, we review ADCA caused by mutations other than polyglutamine expansions (i.e. "non-polyglutamine diseases"). We also describe the neuropathology of chromosome 16q22.1-linked ADCA, which appears to be the most common non-polyglutamine disease in Japan. What we find to be characteristic on the chromosome 16q22.1-linked ADCA brain is the presence of atrophic Purkinje cells surrounded by the formation of amorphous material, the latter composed of the Purkinje cell dendrites stemming from the cell bodies, the presynaptic terminals innervated by certain neurons, and the astroglial processes. Such neuropathological findings seem to be unique for this disease.
Aged↗
In vivo delivery of small interfering RNA targeting brain capillary endothelial cells.
Brain capillary endothelial cells (BCECs) play an important role in blood-brain barrier (BBB) functions and pathophysiologic mechanisms in brain ischemia and inflammation. We try to suppress gene expression in BCECs by intravenous application of small interfering RNA (siRNA). After injection of large dose siRNA with hydrodynamic technique to mouse, suppression of endogenous protein and the BBB function of BCECs was investigated. The brain-to-blood transport function of organic anion transporter 3 (OAT3) that expressed in BCECs was evaluated by Brain Efflux Index method in mouse. The siRNA could be delivered to BCECs and efficiently inhibited endogenously expressed protein of BCECs. The suppression effect of siRNA to OAT3 is enough to reduce the brain-to-blood transport of OAT3 substrate, benzylpenicillin at BBB. The in vivo siRNA-silencing method with hydrodynamic technique may be useful for the study of BBB function and gene therapy targeting BCECs.
Animals↗
Transition of areas of eosinophilic neurons and reactive astrocytes to delayed cortical infarcts after transient unilateral forebrain ischemia in Mongolian gerbils.
The fate of postischemic tissues containing eosinophilic neurons (ENs), whether they remain viable or evolve into infarction, is largely unknown. We analyzed the time profile and distribution of ENs, reactive astrocytes (RAs), and infarction after transient cerebral ischemia. Unilateral forebrain ischemia was induced in Mongolian gerbils by two 10-min unilateral common carotid artery occlusions with a 5-h interval, and the brains at 24 h, 4 days, and 2, 4, and 16 weeks were prepared for morphometric analysis. Intra-ischemic laser Doppler flowmetry revealed significant ischemia, deeper in the anterior cortex, during carotid occlusion. Here, ENs appeared in the middle and deep layers at 24 h postischemia, and EN areas had extended to all cortical layers by 4 days. Large areas of high EN density turned into infarcts between 4 days and 4 weeks. In the posterior cortex, middle and deep cortical layers evolved low EN density areas without subsequent transformation into infarcts. RAs were consistently observed in areas with ENs, and RA areas with high EN density were largely transformed into infarcts between 4 days and 4 weeks postischemia. Areas of high, but not low, EN density were slowly transformed into infarcts after transient cerebral ischemia. Delayed astrocytic death took place in the RA areas with high EN density. In conclusion, density of ENs is an important indicator of delayed astrocytic death and infarction in postischemic tissue.
Animals↗
Transgenic small interfering RNA halts amyotrophic lateral sclerosis in a mouse model.
Many autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with copper/zinc superoxide dismutase (SOD1) mutation may be induced by missense point mutations that result in the production of proteins with toxic properties. Reduction in the encoding of proteins from such mutated genes can therefore be expected to improve the disease phenotype. The duplex of 21-nucleotide RNA, known as small interfering RNA (siRNA), has recently emerged as a powerful gene silencing tool. We made transgenic (Tg) mice with modified siRNA, which had multiple mismatch alternations within the sense strand, to prevent the "shutdown phenomenon" of transgenic siRNA. Consequently, the in vivo knockdown effect of siRNA on SOD1 expression did not diminish over four generations. When we crossed these anti-SOD1 siRNA Tg mice with SOD1G93A Tg mice, a model for ALS, siRNA prevented the development of disease by inhibiting mutant G93A SOD1 production in the central nervous system. Our findings clearly proved the principle that siRNA-mediated gene silencing can stop the development of familial ALS with SOD1 mutation.
Amyotrophic Lateral Sclerosis↗
More than a 100-fold increase in immunoblot signals of laser-microdissected inclusion bodies with an excessive aggregation property by oligomeric actin interacting protein 2/D-lactate dehydrogenase protein 2.
We established a histobiochemical approach targeting micron-order inclusion bodies possessing extensive aggregation properties in situ by using a nonchemical denaturant (oligomeric actin interacting protein 2/d-lactate dehydrogenase protein 2 [Aip2p/Dld2p]) with the combinatorial method of laser-microdissection and immunoblot analysis. As a model, pick bodies were chosen and laser-microdissected from three different brain regions of two patients with Pick's disease. Initially, 500 to 2000 pick bodies were applied onto SDS-PAGE gels after boiling in Laemmli's sample buffer according to established immunoblotting procedures; however, only faint signals were obtained. Following negative results with chemical denaturants or detergent, including 6 M guanidine hydrochloride, 8 M urea, and 2% SDS, the laser-microdissected pick bodies were pretreated with oligomeric Aip2p/Dld2p, which possesses robust protein unfolding activity under biological conditions. Strikingly, only one pick body was sufficient to illustrate an immunoblot signal, indicating that pretreatment with oligomeric Aip2p/Dld2p enhanced the immunoblot sensitivity by more than 100-fold. Pretreatment with oligomeric Aip2p/Dld2p also allowed us to quantify the total protein content of pick bodies. Thus, use of oligomeric Aip2p/Dld2p significantly contributed toward the acquisition of information pertaining to the molecular profile of proteins possessing an extensive aggregation property, particularly in small amounts.
Aged↗