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N Nukina

Publications and source records attributed to N Nukina.

At least 19 recordsLinked to original sources
PubMed1997

Machado-Joseph disease gene product identified in lymphocytes and brain.

Machado-Joseph disease (MJD) is associated with the expansion of an unstable CAG repeat. The existence of an abnormal gene product in MJD was previously suggested with the expanded polyglutamine stretch-specific antibody. However, the product of the normal allele has not previously been identified. We generated monoclonal antibodies against the fusion protein (codon 225-310) of the MJD gene product and then identified the MJD1 gene product in normal lymphoblastoid cells as a approximately 50-kDa protein by immunoblot analysis. The electrophoretic mobility differences among the normal allele products corresponds to the molecular size difference produced by the polyglutamine stretch and the polymorphism at the C-terminus. Moreover, abnormal immunoreactive bands which were larger than the normal ones were found as a approximately 60-kDa protein exclusively in the MJD samples. The cytoplasm and the nuclei of neurons and glial cells were stained by these antibodies with immunocytochemistry. As in other CAG repeat diseases, the abnormal and normal allele products were almost equally expressed in lymphoblastoid cells and the brain of MJD patients.

Alleles↗
PubMed1997

Expression of dentatorubral-pallidoluysian atrophy (DRPLA) proteins in patients.

The genetic defect dentatorubral-pallidoluysian atrophy (DRPLA) is caused by expansion of a CAG trinucleotide repeat. The mutant gene is translated into protein whose electrophoretic mobility correlates to the number of expanded CAG trinucleotide repeats, indicating that the protein carries an expanded glutamine repeat. Using two polyclonal antibodies raised against the DRPLA gene product in immunoblotting, we determined the untruncated DRPLA proteins, and showed that the amounts of mutant and wild-type DRPLA proteins were similar in DRPLA brain tissues and lymphoblastoid cells, suggesting that regulation of the level of translation of the DRPLA gene is not central to the development of the disease.

Adult↗
PubMed1997

Huntington's disease gene product, huntingtin, associates with microtubules in vitro.

The gene responsible for Huntington's disease produces a large protein with a molecular weight of approximately 350 k, designated huntingtin. Here, we report that the protein can associate in vitro with the microtubules. Through the process of assembly and disassembly of microtubules, both wild-type and mutant huntingtin associate with microtubules to almost the same degree. Huntingtin does not bind to the tubulin-affinity column directly. Huntingtin appears to interact with polymerized tubulin. These results suggest that huntingtin may have a role in intracellular organelle transport or axonal transport by its association with microtubules.

Adult↗
PubMed1997

Fatal GVHD demonstrating an involvement of respiratory muscle following donor leukocyte transfusion (DLT).

A 41-year-old female patient with AML, who relapsed after an allogeneic BMT from her HLA-identical sister, was treated by a donor leukocyte transfusion (DLT). Thereafter, bone marrow aplasia accompanied by the disappearance of leukemic blasts following the GVHD was observed. The patient died of chronic GVHD with respiratory muscle involvement 19 months after the DLT. Although the DLT was considered helpful in suppressing the proliferation of the leukemic cells, it might also have caused the severe GVHD observed in this case. Efforts to separate the lymphocyte clones responsible for GVL from those for the GVHD thus appear to be necessary for the further development of the therapeutic approach, so-called DLT.

Adult↗
PubMed1997

Unusual MRI and pathologic findings of progressive multifocal leukoencephalopathy complicating adult Wiskott-Aldrich syndrome.

We present a long-surviving patient with Wiskott-Aldrich syndrome complicated by atypical progressive multifocal leukoencephalopathy (PML). MRI showed multiple tiny spots of Gd-DTPA-enhanced lesions on the T1-weighted image. Pathologic findings for brain biopsy were patchy demyelinated vascularized lesions infiltrated by a surprising number of eosinophils. The presence of polyomavirus JC was confirmed by in situ hybridization and polymerase chain reaction. PML should be included in the differential diagnosis when Gd-DTPA-enhanced spotty lesions are present in the white matter, especially in patients who have a mild immunologic defect.

Adult↗
PubMed1996

Characterization of dentatorubral-pallidoluysian atrophy proteins using two-dimensional electrophoretic analysis.

The genetic defect dentatorubral-pallidoluysian atrophy (DRPLA) is known to be an expansion of a CAG trinucleotide repeat. The mutant gene has been demonstrated to be translated into protein, and this protein contains an expanded polyglutamine region. In the present study, we have demonstrated using two-dimensional gel electrophoresis and immunoblotting that the DRPLA gene products consist of a number of isoelectric variants in brain tissue and lymphoblastoid cells. The identification of isoelectric variants indicates that there may be multiple stages of post-translational modification. DRPLA proteins from brain tissue possess fewer basic isoelectric variants than those from lymphoblastoid cells, suggesting that there is different post-translational modification steps in brain tissue and lymphoblastoid cell.

Adolescent↗
PubMed1996

PET analysis of a case of cerebrotendinous xanthomatosis presenting hemiparkinsonism.

We describe a 34-year-old Japanese woman presenting gait difficulty and Achilles tendon swelling. The patient was diagnosed as having cerebrotendinous xanthomatosis (CTX) based on the high serum cholestanol level and diminished enzymatic activity of 27-hydroxylase of fibroblasts from her skin. Her clinical presentation was atypical regarding the presence of hemiparkinsonism and absence of apparent cataract, dementia, and cerebellar ataxia. Although MRI studies could not detect any abnormality in the basal ganglia or midbrain, PET analysis using [18F]-6-fluoro-L-dopa revealed reduced uptake of dopamine into the putamen, suggesting the impairment of presynaptic dopaminergic neurons.

Adult↗
PubMed1996

A unique origin and multistep process for the generation of expanded DRPLA triplet repeats.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder associated with the expansion of a CAG repeat at chromosome band 12p13. Epidemiological studies have demonstrated an increased prevalence of DRPLA in Japan, although several DRPLA kindreds of non-Japanese ancestry have been identified. To define the molecular basis for this geographic variation in prevalence, we have analyzed haplotypes around the repeat in several different ethnic groups. Two intragenic biallelic polymorphisms distinguished three haplotypes, each of which formed a predominant haplotype found in the three major racial populations. All the expanded repeats of Japanese and Caucasian patients studied were associated with a particular haplotype, which otherwise was associated with longer repeats commonly found in Asians. Our results support a multi-step model for repeat expansion, and suggest that expanded DRPLA repeats may have evolved from an ancient chromosomal haplotype of Asian origin. We also propose that a combination of a highly polymorphic microsatellite marker with relatively stable biallelic markers in a range of PCR amplification is a powerful tool for studies on human genome diversity, which may reveal the ancient human migration and the formation of ethnic groups.

Black or African American↗
PubMed1996

Cortical dysgenesis in a patient with Turner mosaicism.

In a patient with Turner mosaicism who had mental retardation, epilepsy and cerebellar ataxia, MRI showed cerebellar atrophy and a bizarre cortical dysgenesis of the cerebrum, which was considered to comprise a mixture of relatively normal gyri and structures resembling pachygyria and lissencephaly. The karyotype of the patient was 45,X/47,XXX, but the brain dysgenesis could not be explained solely on the basis of this mosaicism, which is rarely associated with a gross abnormality in brain pathology. Abnormality of the X chromosome seems to have some potential for inducing cortical dysgenesis, and this case may be partially attributable to an abnormal locus on the X chromosome.

Adult↗
PubMed1996

Dentatorubral-pallidoluysian atrophy proteins in lymphoblastoid cells.

The genetic defect responsible for dentatorubral-pallidoluysian atrophy (DRPLA) is an expansion of a CAG trinucleotide repeat. The DRPLA gene is translated into protein in the brain. In this study, we demonstrate that the wild-type and mutant genes are also translated into proteins, p190 and p205, in lymphoblastoid cells. The correlation between the age of onset and the expansion of polyglutamine stretch shown by slower electrophoretic mobility suggests that the polyglutamine stretch is directly involved in the acceleration of the disease process. Moreover, analysis of the protein in lymphoblastoid cells can be used as a diagnostic procedure for DRPLA.

Adult↗
PubMed1995

Monoclonal antibody against the polymorphic site distinguishes apolipoprotein E4 from other isoforms.

Apolipoprotein E4 has been confirmed as a genetic risk factor for Alzheimer's disease. Although several hypotheses have been advanced to explain how the inheritance of apolipoprotein E isoforms affects the rate of Alzheimer's disease expression, the mechanism whereby apolipoprotein E is involved in the pathogenesis of Alzheimer's disease is still uncertain. To clarify the way in which the apolipoprotein E4 isoform differs from the others, we generated a monoclonal antibody specifically reactive with the apolipoprotein E4 isoform. This antibody suggests that the polymorphic site is important in differentiating the ApoE4 isoform from others.

Alzheimer Disease↗
PubMed1995

Abnormal gene product identified in Huntington's disease lymphocytes and brain.

Huntington's disease(HD) is associated with expansion of an unstable CAG repeat. Using antibodies against the synthetic peptide corresponding to the sequence of HD gene IT15, we have identified the HD gene product in normal lymphocytes as a approximately 350kDa protein by immunoblot analysis. Moreover, when a modified SDS-PAGE using a low concentration of methylenbisacrylamide was run longer, abnormal immunoreactive bands larger than normal ones were found exclusively in HD samples. These results demonstrate the existence of the expanded CAG repeat gene product and open a possibility that the expanded polyglutamine stretch may really participate in the pathological process of the CAG repeat diseases.

Amino Acid Sequence↗
PubMed1995

Abnormal gene product identified in hereditary dentatorubral-pallidoluysian atrophy (DRPLA) brain.

Dentatorubral-pallidoluysian atrophy (DRPLA) is associated with the expansion of an unstable CAG repeat. Using antibodies against a synthetic peptide corresponding to the sequence of the DRPLA gene product C terminus, we have identified the DRPLA gene product in normal human brains as a approximately 190 kD protein. We also find a larger approximately 205 kD protein specifically in DRPLA brains. Immunohistochemically, the DRPLA gene product is observed mainly in the neuronal cytoplasm. Our results demonstrate the existence of the expanded CAG repeat gene product and support the possibility that the expanded CAG-encoded polyglutamine stretch may participate in the pathological process of the similar trinucleotide repeat diseases.

Adult↗
PubMed1995

[Dementia].

Explore the source record for details and available documents.

Aged↗
PubMed1995

[Huntington's disease: trinucleotide disease or polyglutamine disease?].

Huntington's disease (HD) is associated with expansion of an unstable CAG repeat. Using antibodies against the synthetic peptide corresponding to the sequence of HD gene IT15, we have identified the HD gene product in normal lymphocytes as a approximately 350kDa protein by immunoblot analysis. Moreover, when a modified SDS-PAGE using a low concentration of methylenbisacrylamide was run longer, abnormal immunoreactive bands larger than normal ones were found exclusively in HD samples. We also found double bands in HD brain homogenate samples. Recently on the other CAG repeat diseases, such as SCA1 and DRPLA, abnormal gene products were also reported. These results demonstrate the existence of the expanded CAG repeat gene products and open a possibility that the expanded polyglutamine stretch may really participate in the pathological process of the CAG repeat diseases.

Humans↗
PubMed1994

APP717 missense mutation affects the ratio of amyloid beta protein species (A beta 1-42/43 and a beta 1-40) in familial Alzheimer's disease brain.

We have biochemically purified A beta from brains of two unrelated familial Alzheimer's disease (FAD) pedigrees with the APP717 mutation (Val-->Ile) and from two sporadic Alzheimer's disease (AD) brains and characterized them by means of mass spectrometry and enzyme-linked immunosorbent assay. We observed two types of amyloid beta protein (A beta), the short-tail form (A beta 1-40) and the long-tail form (A beta 1-42/43), in sporadic AD and FAD brains, and found that the ratio of the long-tail form of A beta (A beta 1-42/43) to total A beta was increased in FAD brains. These in vivo results were confirmed in vitro using cultured cells transfected with three kinds of APP cDNAs bearing the APP717 mutations (Val-->Ile, Gly, or Phe). Taken together with the hypothesis that A beta 1-42/43 functions as a "seed" that increases the kinetics of amyloid fibril formation (Jarrett, J. T., and Lansbury, P. T., Jr. (1993) Cell 73, 1055-1058), we conclude that the APP717 missense mutation does not create new A beta species but promotes the increased accumulation of A beta 1-42/43 in the brain, which results in the enhancement of amyloid fibril formation from soluble A beta. These findings provide a causal relationship between this FAD genotype and the pathological phenotype of A beta deposition and senile plaque formation.

Adult↗
PubMed1994

Cerebellar ataxia and polyneuropathy in a patient with IgM M-protein specific to the Gal(beta 1-3)GalNAc epitope.

A 79-year-old man with sensory dominant polyneuropathy, cerebellar ataxia, and palatal myoclonus had serum IgM M-protein that specifically bound to GM1, GD1b, and asialo-GM1. IgM with the same specificity was detected in his cerebrospinal fluid. Results of immunohistochemical studies showed specific binding of this monoclonal IgM to the cerebellar granular layer, dentate nucleus, inferior olive, and gray matter of the cerebrum and spinal cord. Monoclonal antibody GGR12, monospecific to GD1b, had an immunostaining distribution similar to that of the patient's IgM M-protein. The binding of M-protein may be associated with the development of cerebellar ataxia and palatal myoclonus in this patient.

Aged↗