Search PubMed⌕ Search

Biomedical subjects

G Sobue

Publications and source records attributed to G Sobue.

At least 109 records · Page 6Linked to original sources
PubMed1999

Expression of GDNF receptor (RET and GDNFR-alpha) mRNAs in the spinal cord of patients with amyotrophic lateral sclerosis.

The mRNA levels of RET and GDNFR-alpha were studied in the spinal cord of patients with amyotrophic lateral sclerosis (ALS) by reverse transcription followed by polymerase chain reaction (RT-PCR) and in situ hybridization (ISH). Semiquantitative RT-PCR analysis revealed that RET mRNA levels in the ALS spinal cord anterior horn were reduced to one fifth of controls in proportion to motor neuron loss, whereas GDNFR-alpha mRNA was unchanged. ISH analysis showed that RET mRNA was expressed in the anterior horn motor neurons of the spinal cord, but GDNFR-alpha mRNA was expressed widely in the spinal cord neurons and glial cells. The RET mRNA levels, measured using a CCD image analyzer, were substantially preserved in individual motor neurons of ALS, but varied among those neurons. Relatively high levels of RET mRNA were observed in a certain population of atrophic neurons. On the other hand, the GDNFR-alpha mRNA levels in the motor neurons were similar in ALS and controls. In addition, the RET protein was also well expressed in individual motor neurons in ALS. These results indicate that GDNF receptor expression persists at mRNA and protein levels in the degenerating motor neurons in ALS, supporting the view that GDNF is a candidate for therapeutic approach to ALS.

Aged↗
PubMed1999

Clinical and physiological characteristics of autonomic failure with Parkinson's disease.

We analyzed the clinical and physiological features of autonomic failure with Parkinson's disease (AF-PD) in seven patients and compared them with those of autonomic failure with multiple system atrophy (AF-MSA). In AF-PD, parkinsonism was more gradually progressive than in AF-MSA, and symptoms were responsive to L-dopa. All seven patients with AF-PD had orthostatic hypotension, postprandial hypotension, and constipation, but no urinary retention. Of these, three had hypohidrosis and five had frequent urination; five patients had subnormal plasma norepinephrine (NE) concentrations. Supersensitivity to NE infusion was observed in all patients. Head-up tilting (HUT) test resulted in no increase of plasma NE concentrations in both groups, but a significant increase of the plasma arginine vasopressin (AVP) concentrations in the patients with AF-PD. Urodynamic studies revealed that urinary bladder function was relatively well preserved in AF-PD in contrast to AF-MSA. In conclusion, there exists some clinical and physiological differences in autonomic features between AF-PD and AF-MSA, and postganglionic involvement predominates in AF-PD.

Aged↗
PubMed1999

Age-related morphologic changes of the central canal of the human spinal cord.

To elucidate the role of the human central canal on the physiology and pathogenesis of acquired syringomyelia, we analyzed the age-related morphologic changes in the normal human central canal of the spinal cord. The subjects included 158 autopsy cases ranging in age from 1 week postnatally to 116 years of age. Each segment of the whole spinal cords was investigated from the C3 to S3 levels. The microscopic pictures of the central canal were classified as patent or occluded at each level for each age decade. The patency rate under 1 year of age was 100% in almost all the segments, which markedly decreased in the second decade, and the canals were occluded in all the segments with advancing age. According to the longitudinal pattern of the central canal occlusion, 19 of 20 cases where the canals were patent in all segment levels were less than 10 years of age. Cases in which the canals were occluded in all segment levels appeared in the second decade, and their number increased gradually with advancing age. The occlusion of the central canal started at the T6 and L5 to S2 levels. We suggest that the central canal does not function after infancy because of its occlusion, and that it is not involved in the development of syringomyelia in adult patients.

Adolescent↗
PubMed1999

Expression of GDNF and GDNFR-alpha mRNAs in muscles of patients with motor neuron diseases.

The mRNA expression levels of GDNF, GDNFR-alpha and RET were examined in the muscles of amyotrophic lateral screlosis (ALS) and X-linked spinal and bulbar muscular atrophy (SBMA). GDNF mRNA levels were significantly elevated to variable extent in the diseased muscles compared to control muscles, although they were not specific to the type of the diseases. The diseased muscles also have a different expression pattern of GDNF mRNA isoforms from controls. GDNF mRNA expression, however, tended to reduce in advanced muscle pathology. On the other hand, GDNFR-alpha mRNA levels were not changed significantly on expression levels in the diseased muscles. In situ hybridization study revealed that GDNF and GDNFR-alpha mRNAs were localized in subsarcolemmal space of muscle cells. RET mRNA was not detected in control nor diseased muscles. These results suggest that the elevated muscle GDNF acts as a trophic signal for motor neurons of motor neuron diseases, implying a possible therapeutic implication of GDNF to this type of diseases.

Drosophila Proteins↗
PubMed1999

Triggering of neuronal cell death by accumulation of activated SEK1 on nuclear polyglutamine aggregations in PML bodies.

BACKGROUND: A novel class of inherited human neurodegenerations is now known to be caused by expanded CAG repeats encoding polyglutamines. Polyglutamine-containing protein fragments have been shown to accumulate as aggregates in the nucleus and in the cytoplasm, and to induce cell death when expressed in cultured cells, leading to the proposal that polyglutamine aggregation is an important step in the pathogenesis. Supporting this, nuclear inclusions containing expanded polyglutamines have been identified in neurones from the brains of patients and in neurones from transgenic mouse models of this class of neural disorders. RESULTS: We analysed the consequences of polyglutamine expression in PC12 neuronal cells. Activated SEK1 accumulated with nuclear but not cytoplasmic polyglutamine aggregations, which consequently triggers cell death. Cell death induced by polyglutamine expression was inhibited by a dominant-negative SEK1 (DN-SEK1), but not by DN-SEK1 tagged with a nuclear export signal. Steady state SEK1 expression itself was enhanced two to three-fold. Nuclearly aggregated polyglutamines, which were identified in PML bodies, co-localized with not only activated SEK1 but also activated c-Jun. We also observed that nuclear inclusion-positive neurones from brains with Huntington's disease expressed SEK1. CONCLUSIONS: This study provides molecular links between the neurodegeneration observed in polyglutamine diseases, cell death signalling kinase cascades and nuclear subdomains related to cell death. We propose that the nuclear PML bodies containing polyglutamine aggregates activate the SEK1-JNK kinase cascade, resulting in the transduction of a death signal.

Animals↗
PubMed1999

Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level.

The factors influencing the tissue-specific pattern of somatic mosaicism in CAG-repeat diseases have not yet been fully resolved. We performed a detailed analysis of the degree of somatic mosaicism in various tissues from 20 patients with spinal and bulbar muscular atrophy (SBMA), including 4 who were deceased. The most outstanding feature was the prominent somatic mosaicism observed in the cardiac and skeletal muscles, composed predominantly of postmitotic cells, and in the skin, prostate, and testis. The CNS tissues, liver, and spleen showed the least mosaicism. The tissue distribution of somatic mosaicism in patients with SBMA was markedly different from that in patients with Huntington disease (HD) and from that in patients with dentatorubral-pallidoluysian atrophy (DRPLA). The degree of somatic mosaicism correlated with the CAG-repeat number but not with age at examination. Furthermore, tissues with a higher mosaicism level corresponded well to those with a higher expression level of androgen receptor protein. The tissue-specific pattern of somatic mosaicism related not only to cell composition with different cell turnover rates but to repeat size and gene expression levels, and postnatal cell division is unlikely to be a major cause of somatic mosaicism probably because of the relative stability of CAG repeat in SBMA.

Adult↗
PubMed1999

Late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy) unrelated to endemic focus in Japan. Clinicopathological and genetic features.

Clinicopathological and genetic features were assessed on 35 Japanese families affected by late-onset familial amyloid polyneuropathy type I (transthyretin Met30-associated familial amyloid polyneuropathy, FAP TTR Met30) whose siblings were unrelated to endemic Japanese foci. In these patients (50 years or older), the most common initial symptom was paraesthesias in the legs. Autonomic symptoms were generally mild and did not seriously affect daily activities. The male-to-female ratio was extremely high (10.7 : 1). A family history was evident in only 11 out of 35 families, and other patients were apparently sporadic. The rate of penetrance was very low. Symptomatic siblings of familial cases showed a late age of onset, male preponderance and clinical features similar to those of the probands. Asymptomatic carriers, predominantly female, were detected relatively late in life. The geographical distribution of these late-onset, FAP TTR Met30 cases was scattered throughout Japan. In three autopsy cases and 20 sural nerve biopsy specimens, neurons in sympathetic and sensory ganglia were relatively preserved. Amyloid deposition was seen in the peripheral nervous system, particularly in the sympathetic ganglia, dorsal root ganglia and proximal nerve trunks such as sciatic nerve. These abnormalities were milder than those seen in typical early-onset FAP TTR Met30, as observed in two Japanese endemic foci of this disease. While axonal degeneration was prominent in myelinated fibres, resulting in severe fibre loss, unmyelinated fibres were relatively preserved. Our cases of late-onset FAP TTR Met30 showed features distinct from those of typical early-onset FAP TTR Met30 that occurred in the two Japanese endemic foci. Factors responsible for clinicopathological differences between these two forms of FAP TTR Met30 need to be identified.

Action Potentials↗
PubMed1999

Clinicopathological features of Churg-Strauss syndrome-associated neuropathy.

We assessed the clinicopathological features of 28 patients with peripheral neuropathy associated with Churg-Strauss syndrome. Initial symptoms attributable to neuropathy were acute painful dysaesthesiae and oedema in the dysaesthetic portion of the distal limbs. Sensory and motor involvement mostly showed a pattern of mononeuritis multiplex in the initial phase, progressing into asymmetrical polyneuropathy, restricted to the limbs. Parallel loss of myelinated and unmyelinated fibres due to axonal degeneration was evident as decreased or absent amplitudes of sensory nerve action potentials and compound muscle action potentials, indicating acute massive axonal loss. Epineurial necrotizing vasculitis was seen in 54% of cases; infiltrates consisted mainly of CD8-positive suppressor/cytotoxic and CD4-positive helper T lymphocytes. Eosinophils were present in infiltrates, but in smaller numbers than lymphocytes. CD20-positive B lymphocytes were seen only occasionally. Deposits of IgG, C3d, IgE and major basic protein were scarce. The mean follow-up period was 4.2 years, with a range of 8 months to 10 years. Fatal outcome was seen only in a single patient, indicating a good survival rate. The patients who responded well to the initial corticosteroid therapy within 4 weeks regained self-controlled functional status in longterm follow-up (modified Rankin score was < or = 2), while those not responding well to the initial corticosteroid therapy led a dependent existence (P < 0.01). In addition the patients with poor functional outcomes had significantly more systemic organ damage caused by vasculitis (P < 0.05). Necrotizing vasculitis mediated by cytotoxic T cells, leading to ischaemic changes, appears to be a major cause of Churg-Strauss syndrome-associated neuropathy. The initial clinical course and the extent of systemic vasculitic lesions may influence the long-term functional prognosis.

Adult↗
PubMed1999

Transgenic mice harboring a full-length human mutant DRPLA gene exhibit age-dependent intergenerational and somatic instabilities of CAG repeats comparable with those in DRPLA patients.

Dentatorubral-pallidoluysian atrophy (DRPLA) is one among an increasing number of hereditary neurodegenerative diseases determined as being caused by unstable expansion of CAG repeats coding for polyglutamine stretches. To investigate the molecular mechanisms underlying CAG repeat instability, we established three transgenic lines each harboring a single copy of a full-length human mutant DRPLA gene carrying a CAG repeat expansion. These transgenic mice exhibited an age-dependent increase (+0.31 per year) in male transmission and an age-dependent contraction (-1.21 per year) in female transmission. Similar tendencies in intergenerational instabilities were also observed in human DRPLA parent-offspring pairs. The intergenerational instabilities of the CAG repeats may be interpreted as being derived from the instability occurring during continuous cell division of spermatogonia in the male, and that occurring during the period of meiotic arrest in the female. The transgenic mice also exhibited an age-dependent increase in the degree of somatic mosaicism which occurred in a cell lineage-dependent manner, with the size range of CAG repeats being smaller in the cerebellum than in other tissues including the cerebrum, consistent with observations in autopsied tissues of DRPLA patients. Thus, the transgenic mice described in this study exhibited age-dependent intergenerational as well as somatic instabilities of expanded CAG repeats comparable with those observed in human DRPLA patients, and are therefore expected to serve as good models for investigating the molecular mechanisms of instabilities of CAG repeats.

Adult↗
PubMed1999

Axonal and perikaryal involvement in chronic inflammatory demyelinating polyneuropathy.

OBJECTIVES: To assess the extent of loss of myelinated nerve fibres and spinal motor neuron loss in chronic inflammatory demyelinating polyneuropathy (CIDP), a clinicopathological study was conducted on biopsied sural nerves and necropsied spinal cords from patients with CIDP. METHODS: The myelinated fibre pathology of 71 biopsied sural nerves and motor neuron pathology of nine necropsied spinal cords at L4 levels in patients with CIDP were quantitatively and immunohistochemically assessed. RESULTS: Myelinated nerve fibre density was significantly diminished to 65.4% of the control values (p <0.0001), correlating inversely with the extent of segmental demyelination and remyelination (r = -0.43, p < 0.0005) and duration of illness (r = -0.31, p < 0.01). Numbers of large spinal motor neurons in CIDP were variably but significantly diminished (range from 46.0 to 97.6% of the age matched control value (p < 0.005)), and reactive astrogliosis was evident in the ventral horn in CIDP. The frequency of ventral horn neurons exhibiting central chromatolysis and the accumulation of phosphorylated high molecular weight neurofilament protein was significantly higher in CIDP than in controls (p<0.01 and p<0.05). CONCLUSIONS: The loss of nerve axons and spinal motor neurons is common in CIDP, and extensive in some cases. These neuronal and axonal losses may influence the functional prognosis in CIDP.

Adolescent↗
PubMed1999

[Somatic mosaicism of expanded CAG trinucleotide repeat in the neural and nonneural tissues of Machado-Joseph disease (MJD)].

The tissue-specific pattern of somatic mosaicism in Machado-Joseph disease (MJD) was reviewed. In the MJD central nervous system (CNS) tissues, the pattern of CAG repeat mosaicism in the mutant allele was similar among various portions except cerebellar cortex which had slightly smaller CAG repeat tracts. Among nonneural tissues, the muscle exhibited a lesser degree of CAG instability, while the liver, kidney and colon displayed a greater diversity of extra bands and more extended major band compared to CNS. Thus, mitotic turnover may contribute largely to the tissue-specific pattern of mosaicism in MJD, but other unknown cell specific factors should be taken into consideration for the understanding the mechanism of somatic mosaicism in CAG repeat diseases.

Animals↗
PubMed1999

[Somatic mosaicism of CAG repeats size in the nervous system of dentatorubral-pallidoluysian atrophy (DRPLA)].

The somatic mosaicism of CAG repeat expansion in the neural tissues of a dentatorubral-pallidoluysian atrophy (DRPLA) was reviewed. The size of the major bands of the expanded allele was significantly smaller in the cerebellar cortex, however no significant difference was recognized in other regions of neuronal tissues. This showed that severity of neuropathological involvement in DRPLA is not parallel to the size of the expanded allele, indicating somatic mosaicism doesn't explain the selective neurodegeneration in DRPLA. The mechanism underlying the somatic mosaicism remains unknown. However, somatic CAG instability, cell division and some tissue specific factors may closely relate to the occurrence of the somatic mosaicism.

Anticipation, Genetic↗
PubMed1999

[Somatic mosaicism of expanded CAG trinucleotide repeat in spinal and bulbar muscular atrophy (SBMA)].

The CAG repeat in spinal and bulbar muscular atrophy (SBMA) is relatively stable in mitotic and meiotic processes as compared with other CAG repeat diseases. Previous reports indicate that SBMA does not manifest somatic mosaicism. However, detailed analysis in various tissues from 20 SBMA including 4 autopsied patients revealed the presence of the tissue-specific pattern of mosaicism. The prominent somatic mosaicism was observed in the cardiac and skeletal muscles, which are predominantly composed of postmitotic cells, and in the skin, prostate, and testis. The central nervous system (CNS) tissues, liver, and spleen showed smallest mosaicism. Such tissue-specific pattern of somatic mosaicism in SBMA is not explained by cell composition with different cell turnover rates. Other cell specific factors are likely more important for the somatic mosaicism in SBMA.

Humans↗
PubMed1999

[Transcriptional regulation and subcellular localization of mutant androgen receptor in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an adult form of motor neuronopathy with X-linked recessive hereditary trait, whose genetic mutation is an expansion of CAG repeats in the androgen receptor(AR) gene. The effect of the expansion of the polyglutamine stretch in AR protein has been investigated in several lines of experiments. The binding ability of androgen to AR is similar to control, but AR binding affinity to androgen responsive element(ARE) is increased in mutant AR, and AR-induced transcriptional activation decreases with increasing glutamine repeats. The subcellular localization of mutant AR may be variable among the tissues, but intranuclear inclusion of mutant AR occurs ubiquitously in neural and non-neural tissues. Therefore the expansion in the polyglutamine stretch may induce some pathological aberrations in transcriptional regulation and translocation of AR in SBMA.

Adult↗
PubMed1999

[In vitro aggregation and cellular toxicity of mutant androgen receptor protein in spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor caused by expansion of a polyglutamine repeat within the androgen receptor(AR). We have studied the mutant AR in an in vitro system, and find aggregation of the AR protein to occur in a polyglutamine repeat length-dependent manner and the cellular toxicity to be coupled to aggregation. In addition we find intranuclear inclusions in nonneural tissues as well as affected neural tissues. These results indicate that the polyglutamine repeat length-dependent aggregation may be a likely molecular basis for the toxic gain of AR function that produces neuronal degeneration in SBMA. However, there is a recent report which suggests that inclusions did not correlate with cell death. Thus the mechanism of toxic gain of function remains to be elucidated.

Cell Death↗