The Experts below are selected from a list of 1491 Experts worldwide ranked by ideXlab platform
Shoji Tsuji - One of the best experts on this subject based on the ideXlab platform.
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Chapter 16 – Dentatorubral-Pallidoluysian Atrophy (DRPLA)
Genetics of Movement Disorders, 2020Co-Authors: Shoji TsujiAbstract:Publisher Summary Dentatorubral-Pallidoluysian Atrophy (DRPLA) and spinocerebellar ataxia type 17 (SCA17) are rare autosomal dominant neurodegenerative diseases caused by expansion of CAG repeats coding for polyglutamine stretches. Both diseases are characterized by broad spectra of clinical presentations as a function of the size of expanded polyglutamine stretches similarly as have been described in other poly-glutamine diseases. This chapter describes clinical presentations and molecular genetic aspects of DRPLA. DRPLA is clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The striking clinical characteristic features of DRPLA are the considerable heterogeneity in clinical presentation depending on the age of onset and the prominent genetic anticipation. There is no curative therapy for DRPLA. Treatment for DRPLA is essentially palliative. Epilepsies should be treated with anticonvulsants. With availability of animal models, however, it is strongly hoped that the development of new therapeutic approaches are tested using these animal models.
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Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders, Second Edition - Dentatorubral-Pallidoluysian Atrophy.
Handbook of Clinical Neurology, 2011Co-Authors: Shoji TsujiAbstract:Abstract Dentatorubral–pallidoluysian Atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder clinically characterized by various combinations of cerebellar ataxia, choreoathetosis, myoclonus, epilepsy, dementia, and psychiatric symptoms. The most striking clinical features of DRPLA are the considerable heterogeneity in clinical presentation, depending on the age of onset, and the prominent genetic anticipation. DRPLA is caused by unstable expansion of CAG repeats coding for polyglutamine stretches located in exon 5 of the DRPLA gene. DRPLA is characterized by prominent anticipation, with paternal transmission resulting in more prominent anticipation than does maternal transmission, which is now understood based on the intergenerational stability of the CAG repeats. DRPLA protein (also called atrophin-1 ) is localized in the nucleus and functions as a transcription co-regulator. Recent immunohistochemical studies on autopsied tissues of patients with DRPLA have demonstrated that diffuse accumulation of mutant DRPLA protein ( atrophin-1 ) in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), is the predominant pathologic condition and involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. Thus, age-dependent and CAG repeat-dependent intranuclear accumulation of mutant DRPLA leading to nuclear dysfunctions are suggested to be the essential pathophysiologic mechanisms in DRPLA.
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Dentatorubral-Pallidoluysian Atrophy (DRPLA).
Journal of Neural Transmission-supplement, 2007Co-Authors: Shoji TsujiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by expansion of CAG repeats coding for a polyglutamine stretch. The prominent anticipation and broad spectrum in the clinical presentations of DRPLA have been demonstrated to be tightly correlated with the instability of CAG repeats in the DRPLA gene. Discovery of the causative gene for DRPLA has made it possible to investigate molecular mechanisms of neurodegeneration caused by expanded polyglutamine stretches. Recent investigations suggest that nuclear transport of mutant proteins containing expanded polyglutamine stretches and intranuclear aggregate formation play important roles in neuronal degeneration. We have recently demonstrated that the aggregate formation and apoptosis are partially suppressed by trans glutaminase inhibitors, raising the possibility that trans glutaminase is involved in the aggregate body. The results may open new prospects for developing therapeutic measures for the polyglutamine diseases.
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Neuronal Atrophy and synaptic alteration in a mouse model of Dentatorubral-Pallidoluysian Atrophy.
Brain : a journal of neurology, 2006Co-Authors: Kenji Sakai, Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Masahito Yamada, Hitoshi TakahashiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a CAG repeat in the disease protein. Despite the restricted and stable brain lesions, DRPLA patients show a variety of clinical symptoms and the brain exhibits generalized Atrophy. In previous studies of DRPLA, we proposed that intranuclear diffuse accumulation of the mutant protein is a significant pathological feature of neurons, and that the variable prevalence of this pathology may be relevant to the variation of symptoms observed in patients with different repeat sizes. In this study, to elucidate the pathogenesis of the brain Atrophy in DRPLA, we conducted morphological and statistical analyses of neurons affected by the polyglutamine pathology in DRPLA transgenic (Tg) mice with 129 polyglutamine stretches. Golgi-impregnated pyramidal neurons in cerebral cortical layer V of 15-week-old Tg mice showed significant Atrophy of the perikarya and dendrites. Dendritic spines were decreased in number and size, and showed a change in morphology resulting in dominance of stubby spines. Interestingly, dendritic arborization was preserved. Electron microscopy revealed that axons in the pyramis and corpus callosum were also atrophic. The number of axonal microtubules was preserved; however, the inter-microtubule spacing was significantly decreased. In the neuropil of cerebral cortical layers II and III, Atrophy of the pre-synaptic areas and lengths of the post-synaptic density was detected, but synaptic vesicle diameter was preserved. These results suggest that neuronal Atrophy is an essential feature of the cell pathology in DRPLA and that this is closely related to polyglutamine pathogenesis and development of the clinical phenotype.
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Oligodendrocytic polyglutamine pathology in Dentatorubral-Pallidoluysian Atrophy.
Annals of Neurology, 2002Co-Authors: Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Hitoshi TakahashiAbstract:White matter degeneration is one of the pathological conditions of Dentatorubral-Pallidoluysian Atrophy. Autopsy brains exhibited a reduced number of glial cells in the lesions and an involvement of oligodendrocytes in nuclear inclusion formation, which previously has been recognized only as a pathological hallmark in neurons. Dentatorubral-Pallidoluysian Atrophy transgenic mice showed an increased number of affected glias with increasing age and with larger expansions of CAG repeats. These findings suggest that glial cells in Dentatorubral-Pallidoluysian Atrophy also are involved in the polyglutamine pathogenesis.
Hitoshi Takahashi - One of the best experts on this subject based on the ideXlab platform.
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Neuronal Atrophy and synaptic alteration in a mouse model of Dentatorubral-Pallidoluysian Atrophy.
Brain : a journal of neurology, 2006Co-Authors: Kenji Sakai, Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Masahito Yamada, Hitoshi TakahashiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a CAG repeat in the disease protein. Despite the restricted and stable brain lesions, DRPLA patients show a variety of clinical symptoms and the brain exhibits generalized Atrophy. In previous studies of DRPLA, we proposed that intranuclear diffuse accumulation of the mutant protein is a significant pathological feature of neurons, and that the variable prevalence of this pathology may be relevant to the variation of symptoms observed in patients with different repeat sizes. In this study, to elucidate the pathogenesis of the brain Atrophy in DRPLA, we conducted morphological and statistical analyses of neurons affected by the polyglutamine pathology in DRPLA transgenic (Tg) mice with 129 polyglutamine stretches. Golgi-impregnated pyramidal neurons in cerebral cortical layer V of 15-week-old Tg mice showed significant Atrophy of the perikarya and dendrites. Dendritic spines were decreased in number and size, and showed a change in morphology resulting in dominance of stubby spines. Interestingly, dendritic arborization was preserved. Electron microscopy revealed that axons in the pyramis and corpus callosum were also atrophic. The number of axonal microtubules was preserved; however, the inter-microtubule spacing was significantly decreased. In the neuropil of cerebral cortical layers II and III, Atrophy of the pre-synaptic areas and lengths of the post-synaptic density was detected, but synaptic vesicle diameter was preserved. These results suggest that neuronal Atrophy is an essential feature of the cell pathology in DRPLA and that this is closely related to polyglutamine pathogenesis and development of the clinical phenotype.
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Oligodendrocytic polyglutamine pathology in Dentatorubral-Pallidoluysian Atrophy.
Annals of Neurology, 2002Co-Authors: Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Hitoshi TakahashiAbstract:White matter degeneration is one of the pathological conditions of Dentatorubral-Pallidoluysian Atrophy. Autopsy brains exhibited a reduced number of glial cells in the lesions and an involvement of oligodendrocytes in nuclear inclusion formation, which previously has been recognized only as a pathological hallmark in neurons. Dentatorubral-Pallidoluysian Atrophy transgenic mice showed an increased number of affected glias with increasing age and with larger expansions of CAG repeats. These findings suggest that glial cells in Dentatorubral-Pallidoluysian Atrophy also are involved in the polyglutamine pathogenesis.
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Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with Dentatorubral-Pallidoluysian Atrophy.
Annals of Neurology, 2001Co-Authors: Mitsunori Yamada, Shoji Tsuji, Christopher A. Ross, Jonathan D. Wood, Takayoshi Shimohata, Shintaro Hayashi, Hitoshi TakahashiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion. In the present study of DRPLA, we have demonstrated immunohistochemically that diffuse accumulation of mutant atrophin-1 in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. In the neuronal nuclei harboring NIIs, promyelocytic leukemia protein (PML) nuclear bodies were redistributed into a single NII, and the CREB (cAMP-responsive element–binding protein)-binding protein was also recruited into NIIs. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA, and that certain transcriptional abnormalities may be induced secondarily in neuronal nuclei with the formation of NIIs. Ann Neurol 2001;49:14–23
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hereditary dentatorubral pallidoluysian Atrophy ubiquitinated filamentous inclusions in the cerebellar dentate nucleus neurons
Acta Neuropathologica, 1998Co-Authors: Yasuko Hayashi, Mitsunori Yamada, Shoji Tsuji, S. Oyanagi, Haruhiko Naito, Akiyoshi Kakita, Shigekimi Egawa, Hitoshi TakahashiAbstract:We examined the cerebellar dentate nucleus (CDN) in 16 patients with hereditary Dentatorubral-Pallidoluysian Atrophy (DRPLA), one of the neurodegenerative diseases caused by expansion of a CAG repeat encoding a polyglutamine tract in the disease protein. In all patients, some CDN neurons were found to contain ubiquitinated filamentous inclusions in their cytoplasm. On hematoxylin and eosin preparations, these filamentous inclusions were eosinophilic, basophilic or amphophilic, and were often found in areas of pale cytoplasm. Electron microscopy revealed that they consisted of bundles of filaments that were somewhat thicker than neurofilaments. These features of the present inclusions were indistinguishable from those of skein-like inclusions (SLI) previously described in the lower motor neurons in sporadic amyotrophic lateral sclerosis. We conclude that SLI can also occur in the CDN in DRPLA and believe that they reflect a characteristic pathological process in this disease.
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Dentatorubral‐pallidoluysian Atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat
Annals of Neurology, 1995Co-Authors: Takeshi Ikeuchi, Hitoshi Takahashi, Reiji Koide, Hajime Tanaka, Osamu Onodera, Shuichi Igarashi, R. Kondo, Atsushi Ishikawa, Akemi Tomoda, Teruhisa MiikeAbstract:Dentatorubral-Pallidoluysian Atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of Dentatorubral-Pallidoluysian Atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of Dentatorubral-Pallidoluysian Atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of Dentatorubral-Pallidoluysian Atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.
Mitsunori Yamada - One of the best experts on this subject based on the ideXlab platform.
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Dentatorubral-Pallidoluysian Atrophy (DRPLA): The 50th Anniversary of Japanese Society of Neuropathology.
Neuropathology, 2010Co-Authors: Mitsunori YamadaAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a hereditary spinocerebellar degeneration. Despite the establishment of this disease in 1982, it has been pointed out that DRPLA has an unexplained aspect concerning its clinicopathological features; that is, the discrepancy between the variety of clinical manifestations and the uniformity of the brain lesions. The discovery of a causative gene mutation (abnormal expansion of the CAG repeat in DRPLA gene) triggered the development of novel neuropathology in DRPLA, which has suggested that polyglutamine-related pathogenesis involves a wide range of central nervous system regions far beyond the systems previously reported to be affected. It is now likely that DRPLA has an aspect of neuronal storage disorder and has multiple system degeneration, the lesion distribution of which varies depending on the CAG repeat sizes in the causative gene.
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Neuronal Atrophy and synaptic alteration in a mouse model of Dentatorubral-Pallidoluysian Atrophy.
Brain : a journal of neurology, 2006Co-Authors: Kenji Sakai, Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Masahito Yamada, Hitoshi TakahashiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a hereditary spinocerebellar degeneration caused by expansion of a CAG repeat in the disease protein. Despite the restricted and stable brain lesions, DRPLA patients show a variety of clinical symptoms and the brain exhibits generalized Atrophy. In previous studies of DRPLA, we proposed that intranuclear diffuse accumulation of the mutant protein is a significant pathological feature of neurons, and that the variable prevalence of this pathology may be relevant to the variation of symptoms observed in patients with different repeat sizes. In this study, to elucidate the pathogenesis of the brain Atrophy in DRPLA, we conducted morphological and statistical analyses of neurons affected by the polyglutamine pathology in DRPLA transgenic (Tg) mice with 129 polyglutamine stretches. Golgi-impregnated pyramidal neurons in cerebral cortical layer V of 15-week-old Tg mice showed significant Atrophy of the perikarya and dendrites. Dendritic spines were decreased in number and size, and showed a change in morphology resulting in dominance of stubby spines. Interestingly, dendritic arborization was preserved. Electron microscopy revealed that axons in the pyramis and corpus callosum were also atrophic. The number of axonal microtubules was preserved; however, the inter-microtubule spacing was significantly decreased. In the neuropil of cerebral cortical layers II and III, Atrophy of the pre-synaptic areas and lengths of the post-synaptic density was detected, but synaptic vesicle diameter was preserved. These results suggest that neuronal Atrophy is an essential feature of the cell pathology in DRPLA and that this is closely related to polyglutamine pathogenesis and development of the clinical phenotype.
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Oligodendrocytic polyglutamine pathology in Dentatorubral-Pallidoluysian Atrophy.
Annals of Neurology, 2002Co-Authors: Mitsunori Yamada, Toshiya Sato, Shoji Tsuji, Hitoshi TakahashiAbstract:White matter degeneration is one of the pathological conditions of Dentatorubral-Pallidoluysian Atrophy. Autopsy brains exhibited a reduced number of glial cells in the lesions and an involvement of oligodendrocytes in nuclear inclusion formation, which previously has been recognized only as a pathological hallmark in neurons. Dentatorubral-Pallidoluysian Atrophy transgenic mice showed an increased number of affected glias with increasing age and with larger expansions of CAG repeats. These findings suggest that glial cells in Dentatorubral-Pallidoluysian Atrophy also are involved in the polyglutamine pathogenesis.
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Widespread occurrence of intranuclear atrophin-1 accumulation in the central nervous system neurons of patients with Dentatorubral-Pallidoluysian Atrophy.
Annals of Neurology, 2001Co-Authors: Mitsunori Yamada, Shoji Tsuji, Christopher A. Ross, Jonathan D. Wood, Takayoshi Shimohata, Shintaro Hayashi, Hitoshi TakahashiAbstract:Dentatorubral-Pallidoluysian Atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion. In the present study of DRPLA, we have demonstrated immunohistochemically that diffuse accumulation of mutant atrophin-1 in the neuronal nuclei, rather than the formation of neuronal intranuclear inclusions (NIIs), was the predominant pathologic condition and involved a wide range of central nervous system regions far beyond the systems previously reported to be affected. In the neuronal nuclei harboring NIIs, promyelocytic leukemia protein (PML) nuclear bodies were redistributed into a single NII, and the CREB (cAMP-responsive element–binding protein)-binding protein was also recruited into NIIs. The results suggest that the novel lesion distribution revealed by the diffuse nuclear labeling may be responsible for a variety of clinical features, such as dementia and epilepsy in DRPLA, and that certain transcriptional abnormalities may be induced secondarily in neuronal nuclei with the formation of NIIs. Ann Neurol 2001;49:14–23
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Hereditary Dentatorubral-Pallidoluysian Atrophy : detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain
Acta Neuropathologica, 1998Co-Authors: Yasuko Hayashi, Mitsunori Yamada, Takeshi Ikeuchi, Reiji Koide, Shuichi Igarashi, Akiyoshi Kakita, Shigekimi Egawa, Hiroki Takano, Koichi Wakabayashi, Shoji TsujiAbstract:We examined the brains and spinal cords of seven patients with clinicopathologically and genetically confirmed hereditary Dentatorubral-Pallidoluysian Atrophy (DRPLA) using an antibody against ubiquitin, and found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Ubiquitinated neuronal intranuclear inclusions (uNIIs) were consistently found in the striatum, the pontine nuclei, the inferior olivary complex, the cerebellar cortex and the dentate nucleus. Ubiquitinated glial intranuclear inclusions (uGIIs) were found less frequently than uNIIs. Most of the inclusion-bearing nuclei were of an astrocytic nature. Immunostaining with an antibody against DRPLA protein revealed similar immunoreactive neuronal and glial intranuclear inclusions, but in much smaller in numbers compared with uNIIs and uGIIs. Electron microscopy showed that such inclusions were composed of granular and filamentous structures. These findings strongly suggest that, in DRPLA, the occurrence of uNIIs and uGIIs is directly related to the causative gene abnormality (an expanded CAG repeat encoding polyglutamine), that neurons are affected much more widely than previously recognized and that glial cells are also involved in the disease process.
Reiji Koide - One of the best experts on this subject based on the ideXlab platform.
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Hereditary Dentatorubral-Pallidoluysian Atrophy : detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain
Acta Neuropathologica, 1998Co-Authors: Yasuko Hayashi, Mitsunori Yamada, Takeshi Ikeuchi, Reiji Koide, Shuichi Igarashi, Akiyoshi Kakita, Shigekimi Egawa, Hiroki Takano, Koichi Wakabayashi, Shoji TsujiAbstract:We examined the brains and spinal cords of seven patients with clinicopathologically and genetically confirmed hereditary Dentatorubral-Pallidoluysian Atrophy (DRPLA) using an antibody against ubiquitin, and found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Ubiquitinated neuronal intranuclear inclusions (uNIIs) were consistently found in the striatum, the pontine nuclei, the inferior olivary complex, the cerebellar cortex and the dentate nucleus. Ubiquitinated glial intranuclear inclusions (uGIIs) were found less frequently than uNIIs. Most of the inclusion-bearing nuclei were of an astrocytic nature. Immunostaining with an antibody against DRPLA protein revealed similar immunoreactive neuronal and glial intranuclear inclusions, but in much smaller in numbers compared with uNIIs and uGIIs. Electron microscopy showed that such inclusions were composed of granular and filamentous structures. These findings strongly suggest that, in DRPLA, the occurrence of uNIIs and uGIIs is directly related to the causative gene abnormality (an expanded CAG repeat encoding polyglutamine), that neurons are affected much more widely than previously recognized and that glial cells are also involved in the disease process.
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suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated drpla protein with an expanded polyglutamine stretch
Nature Genetics, 1998Co-Authors: Shuichi Igarashi, Mitsunori Yamada, Toshiya Sato, Reiji Koide, Yasuko Hayashi, Mutsuo Oyake, Hiroki Takano, Takayoshi Shimohata, Hidetoshi Date, Aki SatoAbstract:To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (Dentatorubral-Pallidoluysian Atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells. We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri- and intranuclear aggregates and undergo apoptosis. The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases.
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Dentatorubral-Pallidoluysian Atrophy (DRPLA). Molecular basis for wide clinical features of DRPLA.
Clinical Neuroscience, 1995Co-Authors: Takeshi Ikeuchi, Reiji Koide, Osamu Onodera, H. Tanaka, Mutsuo Oyake, Hiroki Takano, Shoji TsujiAbstract:Abstract Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disorder characterized clinically by various combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis, dementia and psychiatric symptoms. Based on the phenomenon of anticipation, the gene for DRPLA was recently identified. DRPLA is caused by unstable expansion of a CAG repeat in the gene located on the short arm of chromosome 12. As have been observed in Huntington's disease and SCA1, there is a strong correlation between the age of onset and the size of CAG repeats. Furthermore, patients with larger repeats tend to show a PME (progressive myoclonus epilepsy) phenotype as well as earlier ages of onset. More prominent anticipation and larger intergenerational increase of CAG repeats in paternal transmission can be accounted for by the meiotic instability of CAG repeats in male gametogenesis. Comparison of size distributions of CAG repeats in Japanese, African-American and white populations revealed that 7.4% of the Japanese alleles had greater than 19 repeats, whereas none of the whites and 1% of the African-American alleles were of this size. The results may account for the ethnic predilection of DRPLA.
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Dentatorubral‐pallidoluysian Atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat
Annals of Neurology, 1995Co-Authors: Takeshi Ikeuchi, Hitoshi Takahashi, Reiji Koide, Hajime Tanaka, Osamu Onodera, Shuichi Igarashi, R. Kondo, Atsushi Ishikawa, Akemi Tomoda, Teruhisa MiikeAbstract:Dentatorubral-Pallidoluysian Atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of Dentatorubral-Pallidoluysian Atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of Dentatorubral-Pallidoluysian Atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of Dentatorubral-Pallidoluysian Atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.
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Dentatorubral-Pallidoluysian Atrophy (DRPLA): Close correlation of CAG repeat expansions with the wide spectrum of clinical presentations and prominent anticipation
Seminars in Cell Biology, 1995Co-Authors: Takeshi Ikeuchi, Reiji Koide, Hajime Tanaka, Osamu Onodera, Mutsuo Oyake, Shoji TsujiAbstract:Abstract Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a rare autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy and dementia as well as various ages of onset. We have identified a specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 as the pathogenic mutation for DRPLA. We investigated how the degree of the expansion of the CAG repeat affects the clinical manifestations of DRPLA. The sizes of the expanded alleles were well correlated with the ages of onset ( r = −0.6955, P
Shuichi Igarashi - One of the best experts on this subject based on the ideXlab platform.
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Hereditary Dentatorubral-Pallidoluysian Atrophy : detection of widespread ubiquitinated neuronal and glial intranuclear inclusions in the brain
Acta Neuropathologica, 1998Co-Authors: Yasuko Hayashi, Mitsunori Yamada, Takeshi Ikeuchi, Reiji Koide, Shuichi Igarashi, Akiyoshi Kakita, Shigekimi Egawa, Hiroki Takano, Koichi Wakabayashi, Shoji TsujiAbstract:We examined the brains and spinal cords of seven patients with clinicopathologically and genetically confirmed hereditary Dentatorubral-Pallidoluysian Atrophy (DRPLA) using an antibody against ubiquitin, and found small, round immunoreactive intranuclear inclusions in both neurons and glial cells in various brain regions. Ubiquitinated neuronal intranuclear inclusions (uNIIs) were consistently found in the striatum, the pontine nuclei, the inferior olivary complex, the cerebellar cortex and the dentate nucleus. Ubiquitinated glial intranuclear inclusions (uGIIs) were found less frequently than uNIIs. Most of the inclusion-bearing nuclei were of an astrocytic nature. Immunostaining with an antibody against DRPLA protein revealed similar immunoreactive neuronal and glial intranuclear inclusions, but in much smaller in numbers compared with uNIIs and uGIIs. Electron microscopy showed that such inclusions were composed of granular and filamentous structures. These findings strongly suggest that, in DRPLA, the occurrence of uNIIs and uGIIs is directly related to the causative gene abnormality (an expanded CAG repeat encoding polyglutamine), that neurons are affected much more widely than previously recognized and that glial cells are also involved in the disease process.
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suppression of aggregate formation and apoptosis by transglutaminase inhibitors in cells expressing truncated drpla protein with an expanded polyglutamine stretch
Nature Genetics, 1998Co-Authors: Shuichi Igarashi, Mitsunori Yamada, Toshiya Sato, Reiji Koide, Yasuko Hayashi, Mutsuo Oyake, Hiroki Takano, Takayoshi Shimohata, Hidetoshi Date, Aki SatoAbstract:To elucidate the molecular mechanisms whereby expanded polyglutamine stretches elicit a gain of toxic function, we expressed full-length and truncated DRPLA (Dentatorubral-Pallidoluysian Atrophy) cDNAs with or without expanded CAG repeats in COS-7 cells. We found that truncated DRPLA proteins containing an expanded polyglutamine stretch form filamentous peri- and intranuclear aggregates and undergo apoptosis. The apoptotic cell death was partially suppressed by the transglutaminase inhibitors cystamine and monodansyl cadaverine (but not putrescine), suggesting involvement of a transglutaminase reaction and providing a potential basis for the development of therapeutic measures for CAG-repeat expansion diseases.
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Dentatorubral‐pallidoluysian Atrophy: Clinical features are closely related to unstable expansions of trinucleotide (CAG) repeat
Annals of Neurology, 1995Co-Authors: Takeshi Ikeuchi, Hitoshi Takahashi, Reiji Koide, Hajime Tanaka, Osamu Onodera, Shuichi Igarashi, R. Kondo, Atsushi Ishikawa, Akemi Tomoda, Teruhisa MiikeAbstract:Dentatorubral-Pallidoluysian Atrophy is an autosomal dominant neurodegenerative disease characterized by various combinations of ataxia, choreoathetosis, myoclonus, epilepsy, and dementia as well as a wide range of ages at onset. A specific unstable trinucleotide repeat expansion in a gene on the short arm of chromosome 12 was recently identified as the pathogenic mutation for this disease. We investigated how the degree of expansion of the CAG repeat affects the clinical manifestations of Dentatorubral-Pallidoluysian Atrophy. The size of the expanded alleles was well correlated with the age at onset (r = -0.696, p < 0.001). Patients with the progressive myoclonus epilepsy phenotype had larger expansions (62-79 repeats) and an earlier age at onset (onset before age 21). Furthermore, most of the patients with the progressive myoclonus epilepsy phenotype inherited their expanded alleles from their affected fathers. On the other hand, patients with the non-progressive myoclonus epilepsy phenotype showed smaller expansions (54-67 repeats) and a later age at onset (onset at or after age 21). Detailed analyses of clinical features demonstrated that ataxia, involuntary movement of either myoclonus or choreoathetosis, and intellectual decline are cardinal features of Dentatorubral-Pallidoluysian Atrophy, with myoclonus and epilepsy being observed more frequently in patients with an earlier age at onset. Thus the wide variation in clinical manifestations of Dentatorubral-Pallidoluysian Atrophy can now be clearly explained based on the degree of CAG repeat expansion, which strongly indicates that the expanded alleles are intimately involved in the neuronal degeneration in dentatofugal and pallidofugal systems.
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Unstable expansion of CAG repeat in hereditary dentatorubral–pallidoluysian Atrophy (DRPLA)
Nature Genetics, 1994Co-Authors: Reiji Koide, Takeshi Ikeuchi, Osamu Onodera, Shuichi Igarashi, R. Kondo, Atsushi Ishikawa, Hidetomo Tanaka, Kotaro Endo, Hideaki Takahashi, Tsunemi HayashiAbstract:Hereditary dentatorubral–pallidoluysian Atrophy (DRPLA) is an autosomal dominant neurologic disorder characterized by variable combinations of myoclonus, epilepsy, cerebellar ataxia, choreoathetosis and dementia. By specifically searching published brain cDNA sequences for the presence of CAG repeats we identified unstable expansion of a CAG in a gene on chromosome 12 in all the 22 DRPLA patients examined. A good correlation between the size of the CAG repeat expansion and the ages of disease onset is found in this group. Patients with earlier onset tended to have a phenotype of progressive myoclonus epilepsy and larger expansions. We propose that the wide variety of clinical manifestations of DRPLA can now be explained by the variable unstable expansion of the CAG repeat.