Shuta Toru

Ataxin-3 is translocated into the nucleus for the formation of intranuclear inclusions in normal and Machado-Joseph disease brains

Machado-Joseph disease (MJD)/spinocerebellar ataxia type 3 (SCA3) is one of the dominantly inherited cerebellar ataxias. The gene responsible for the disease, a novel gene of unknown function, encodes ataxin-3 containing a polyglutamine stretch. Although it has been known that ataxin-3 is incorporated into neuronal intranuclear inclusions (NIIs) in neurons of affected regions, the relationship between NII formation and neuronal degeneration still remains uncertain. In the present study we show two different conditions in which ataxin-3 is recruited into the nucleus and suggest a process to form nuclear inclusions. In normal brains, wild-type ataxin-3 localizes within the ubiquitin-positive nuclear inclusion, the Marinesco body, indicating that ataxin-3 is recruited into the nuclear inclusion even in the absence of pathologically expanded polyglutamine. In MJD/SCA3 brains, immunohistochemical analyses with anti-ataxin-3 antibody, anti-ubiquitin antibody, and monoclonal antibody 1C2 known to recognize expanded polyglutamine revealed differences in frequency and in diameter among NIIs recognized by each antibody. These results were confirmed in the same inclusions by double immunofluorescent staining, suggesting that expanded ataxin-3 forms a core, thereby recruiting wild-type ataxin-3 into the nucleus around the core portion, and then followed by activation of the ubiquitin/ATP-dependent pathway. Recruitment of ataxin-3 into the nucleus and formation of nuclear inclusion under two different conditions suggest that ataxin-3 may be translocated into the nucleus under certain conditions stressful on neuronal cells such as aging and polyglutamine neurotoxicity.

Cytoplasmic and nuclear polyglutamine aggregates in SCA6 Purkinje cells

Aggregations of the alpha1A-calcium channel protein have been previously demonstrated in spinocerebellar ataxia type 6 (SCA6). Here the authors show that small aggregates, labeled by a monoclonal antibody 1C2 that preferentially detects expanded polyglutamine larger than that in SCA6 mutation, are present mainly in the cytoplasm but also in the nucleus of Purkinje cells. Although the length of expansion is small in SCA6, the current finding might indicate that SCA6 conforms to the pathogenic mechanism(s) in other polyglutamine diseases.

A clinical, genetic, and neuropathologic study in a family with 16q-linked ADCA type III.

Presented is the new kindred with autosomal dominant cerebellar ataxia linked to chromosome 16q22.1 (16q-ADCA type III) associated with progressive hearing loss. By haplotype analysis, the critical interval was slightly narrowed to three megabase regions between GATA01 and D16S3095. Neuropathologic study of 16q-ADCA type III demonstrated characteristic shrinkage of Purkinje cell bodies surrounded by synaptophysin-immunoreactive amorphous material containing calbindin- and ubiquitin-positive granules.

Quantitative correlation between cardiac MIBG uptake and remaining axons in the cardiac sympathetic nerve in Lewy body disease

Objectives Reduced cardiac meta-iodobenzylguanidine (MIBG) uptake and loss of cardiac sympathetic axons, as its possible anatomical substrate, were both recognised in Lewy body disease (LBD), while their direct correlation has so far remained speculative. Increasing availability of autopsy-confirmed cases of LBD prompted us to quantify residual cardiac sympathetic axons to establish their relationship to cardiac MIBG uptake. Methods We collected cardiac tissue samples from 23 patients with autopsy-confirmed LBD and two non-LBD control patients who underwent 123I-MIBG cardiac scintigraphy in life. Samples of the left ventricular anterior wall were stained with anti-tyrosine hydroxylase (TH) and anti-neurofilament (NF) antibodies as markers of cardiac nerve axons. We quantified the immunolabelled areas and assessed their correlation to standardised heart to mediastinum (H/M) ratios of 123I-MIBG cardiac scintigraphy. Results Cardiac MIBG uptake in the early and delayed phases was reduced in 90.9% and 95.7% of patients with LBD, respectively. The area of TH-immunoreactive axons correlated significantly with the H/M ratio in the early (p=0.036) as well as in the delayed (p=0.018) phases. The area of NF-immunoreactive axons also correlated with the H/M ratio in the early (p=0.003) as well as in the delayed (p=0.001) phases. Conclusions Tight quantitative correlation between cardiac 123I-MIBG uptake and corresponding loss of sympathetic axons in LBD, as established for the first time by this study, provides a scientific basis to confirm the reliability of MIBG cardiac scintigraphy as a powerful clinical tool to detect loss of these axons as a biomarker for the presence of Lewy body disease.

Physical map and haplotype analysis of 16q-linked autosomal dominant cerebellar ataxia (ADCA) type III in Japan

AbstractAutosomal dominant cerebellar ataxia (ADCA) is a group of heterogeneous neurodegenerative disorders. We previously mapped a gene locus for ADCA with pure cerebellar syndrome (ADCA type III) to a 3-cM region in chromosome 16q, and found a common haplotype among affected individuals. This region was exactly within the locus for another ADCA, spinocerebellar ataxia type 4 (SCA4). To identify the gene causing 16q-linked ADCA type III, we constructed a contig with 38 bacterial artificial chromosome clones between D16S3043 and D16S3095. The size of this contig was estimated to be 4.8Mb. We found more than 500 nucleotide tandem repeats, including 9 CAG/CTG repeats in this candidate region, although none of the 94 tandem repeats analyzed were expanded in affected individuals. However, we found 11 new polymorphic markers, giving 22 markers spanning the candidate region. By typing these markers on eight Japanese families with ADCA type III, including two new families, we found that a common “founder” haplotype is seen in a more restricted 3.8-Mb region, spanning markers GGAA05 and D16S3095. We present here a newly refined critical interval of 16q-ADCA type III/SCA4. Data of 11 new DNA markers on 16q22.1 would also be useful for other research of genes mapped to this region.

Autonomic dysfunction and orthostatic hypotention caused by vitamin B12 deficiency

Orthostatic hypotension sometimes is a reversible neurological complication of vitamin B12 deficiency.1 2 Eisenhofer detected deficient sympathetic catecholamine release in insulin tolerance testing,2 but the mechanism of orthostatic hypotension in vitamin B12 deficiency remains unclear. We report a patient with vitamin B12 deficiency and reversible orthostatic hypotension, and discuss the mechanism of this symptom. A 77 year old man admitted to our hospital had had unstable gait and urinary urgency for 6 months, clumsiness of the hands and tingling sensations in the legs for 3 months, and, for a month, occasional dizziness on standing. The dizziness was mild without any attack of syncope. He had no other symptoms or signs of autonomic dysfunction but impotence and erectile failure were noted 10 years before the onset of neurological symptoms. He had not taken any medicine which would affect the autonomic nervous system. He did not have a habit of drinking. Physical examination on admission detected no signs of anaemia, heart failure, or dehydration. …

Redefining the disease locus of 16q22.1-linked autosomal dominant cerebellar ataxia

AbstractThe 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.

Depletion or preservation of cardiac sympathetic nerve - an autopsy-verified contrast in two cases of Alzheimer's disease with or without Lewy bodies.

We report autopsy findings of 2 patients with the clinical diagnosis of dementia with Lewy bodies (DLB) both with Alzheimer disease (AD) pathology. Lewy bodies and cardiac sympathetic nerve depletion were found in case 1, while these pathological changes were both absent in case 2 with pure AD pathology. This autopsy-verified contrast was detectable through reduced uptake of 123I-metaiodobenzylguanidine cardiac scintigraphy as in case 1. Conversely, its preserved uptake, indicating preserved cardiac sympathetic nerve, may point to the absence of Lewy bodies, as in case 2, even though other clinical pictures are indistinguishable from DLB. 123I-metaiodobenzylguanidine cardiac scintigraphy may be useful to distinguish clinically between pure AD and DLB.

Paradoxical cerebral embolism with patent foramen ovale and deep venous thrombosis caused by a massive myoma uteri

A 42-year-old dextral woman came to our hospital with right emiparesis. A huge uteral myoma was found 10 years ago, and he regularly visited our gynecology department. She had had neiher other past illnesses nor the habit of drinking or smoking. Drug istory for oral contraceptives is negative. At age 41, she suddenly uffered left hemiparesis and was admitted to another hospital. erebral infarction was diagnosed in the right middle cerebral rtery (MCA) area. Brain angiography showed stenosis of the M2 ortion of the right MCA, but no atherosclerotic changes. She was ischarged with no neurological symptoms, after which cilostazol ad been prescribed. On admission to our hospital, right hemiparesis and severe otor aphasia were present, and there was slight edema in her left eg. Neurological and general findings showed no other abnormaliies. d-Dimer was elevated to 30.8 g/ml (normal range < 1 g/ml), ut other laboratory data on admission for cholesterol, HbA1c,

Pseudomonous putida meningitis in a healthy adult

JO N 2987 (E3V4M6 on the Glasgow Coma Scale) and slight neck rigidity were present. Neurological and general findings showed no other abnormality. Laboratory data on admission were erythrocyte sedimentation rate 109 mm/1h; white blood cells (WBC) 11,170/mm3; and C-reactive protein (CRP) 6.3 mg/dl. Other laboratory tests, including HbA1c and urine analysis, were normal. HIV antibody was negative. Computerized brain tomography (CT) showed slight brain edema. The open pressure was raised to 300 mmH2O on lumbar puncture on admission. Her cerebrospinal fluid (CSF) was cloudy with 1833/mm3 WBC (78.5 % polymorphonuclear cells), 44 mg/dl glucose (simultaneous blood sugar 130 mg/dl), and 344 mg/dl protein. A chest radiograph and cardioechograph were normal. Her CT of the abdominal, chest, and cervical regions revealed no focus of infection or malignancy. No CSF leakage or sinusitis was found in otolaryngological medical examinations. We immediately started the antibiotics ceftriaxone and vancomycin with dexamethazone, the standard therapy for acute bacterial meningitis. Gram staining of her CSF showed gram negative rods. Because on hospital day two a culture grew the pseudomonas genus, she was placed on ceftazidime and gentamycin. Later, the P. putida found in both her CSF and blood cultures was susceptible to ceftazidime, gentamycin, meropenem and imipenem. Her consciousness slowly improved, becoming clear on hospital day four. Her laboratory data for hospital day two showed a WBC count of 12090/ mm3 and a CRP of 17.6 mg/dl. In the CSF study performed on the same day, her WBC count was 7753/mm3. Subsequent blood and CSF tests showed improvement, and no bacteria were detected in her CSF. Because drug-induced Shuta Toru Tetsuro Maruyama Takumi Hori Naoki Gocho Takayoshi Kobayashi