The Experts below are selected from a list of 282 Experts worldwide ranked by ideXlab platform
Sobue - One of the best experts on this subject based on the ideXlab platform.
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Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine Nuclear Inclusions and neuronal dysfunction without neuronal cell death
Human molecular genetics, 2001Co-Authors: Hiroaki Adachi, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Akito Kume, Hisayoshi Niwa, Chen Sang, SobueAbstract:We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ Nuclear Inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal Inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.
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Nonneural Nuclear Inclusions of androgen receptor protein in spinal and bulbar muscular atrophy
The American journal of pathology, 1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions.
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Short Communication Nonneural Nuclear Inclusions of Androgen Receptor Protein in Spinal and Bulbar Muscular Atrophy
1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of ARpositive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions. (Am J Pathol 1998, 153:695‐701)
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Nuclear Inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
Annals of neurology, 1998Co-Authors: Shigeru Miwa, Diane E Merry, Kenneth H. Fischbeck, Yasushi Kobayashi, Fumiaki Tanaka, Manabu Doyu, Yoshio Hashizume, Masahiko Yamamoto, SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated Nuclear Inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing Nuclear Inclusions are present in SBMA.
Yasushi Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
Neuron, 2002Co-Authors: Masahisa Katsuno, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Hiroaki Adachi, Akito Kume, Hisayoshi Niwa, Chen Sang, Gen SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse Nuclear staining and Nuclear Inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.
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Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine Nuclear Inclusions and neuronal dysfunction without neuronal cell death
Human molecular genetics, 2001Co-Authors: Hiroaki Adachi, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Akito Kume, Hisayoshi Niwa, Chen Sang, SobueAbstract:We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ Nuclear Inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal Inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.
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Nonneural Nuclear Inclusions of androgen receptor protein in spinal and bulbar muscular atrophy
The American journal of pathology, 1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions.
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Short Communication Nonneural Nuclear Inclusions of Androgen Receptor Protein in Spinal and Bulbar Muscular Atrophy
1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of ARpositive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions. (Am J Pathol 1998, 153:695‐701)
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Nuclear Inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
Annals of neurology, 1998Co-Authors: Shigeru Miwa, Diane E Merry, Kenneth H. Fischbeck, Yasushi Kobayashi, Fumiaki Tanaka, Manabu Doyu, Yoshio Hashizume, Masahiko Yamamoto, SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated Nuclear Inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing Nuclear Inclusions are present in SBMA.
Manabu Doyu - One of the best experts on this subject based on the ideXlab platform.
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testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
Neuron, 2002Co-Authors: Masahisa Katsuno, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Hiroaki Adachi, Akito Kume, Hisayoshi Niwa, Chen Sang, Gen SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse Nuclear staining and Nuclear Inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.
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Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine Nuclear Inclusions and neuronal dysfunction without neuronal cell death
Human molecular genetics, 2001Co-Authors: Hiroaki Adachi, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Akito Kume, Hisayoshi Niwa, Chen Sang, SobueAbstract:We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ Nuclear Inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal Inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.
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Nonneural Nuclear Inclusions of androgen receptor protein in spinal and bulbar muscular atrophy
The American journal of pathology, 1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions.
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Short Communication Nonneural Nuclear Inclusions of Androgen Receptor Protein in Spinal and Bulbar Muscular Atrophy
1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of ARpositive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions. (Am J Pathol 1998, 153:695‐701)
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Nuclear Inclusions of the androgen receptor protein in spinal and bulbar muscular atrophy
Annals of neurology, 1998Co-Authors: Shigeru Miwa, Diane E Merry, Kenneth H. Fischbeck, Yasushi Kobayashi, Fumiaki Tanaka, Manabu Doyu, Yoshio Hashizume, Masahiko Yamamoto, SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. To study AR protein expression in normal and SBMA individuals, we used several antibodies that recognize AR protein, and analyzed neural and nonneural tissues by immunohistochemistry and western blotting. Both the normal and the mutant AR proteins were widely distributed, predominantly, but not exclusively, in the cytoplasm of neurons regardless of the pathological involvement, and predominantly in the nuclei of the nonneural tissues in both normal and SBMA individuals, with different expression levels of AR protein among different tissues. In the motor neurons of SBMA patients, there were AR-immunoreactive ubiquitinated Nuclear Inclusions that were detected by antibodies that recognize a small portion of the N terminus of the AR protein. Absence of other immunoreactive AR epitopes within the inclusion may be due to altered AR configuration, or masking of AR epitopes by other proteins, or proteolytic cleavage of the AR. Our data show that, in addition to the normal cellular distribution of the AR protein, mutant AR-bearing Nuclear Inclusions are present in SBMA.
Yuji Nakagomi - One of the best experts on this subject based on the ideXlab platform.
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testosterone reduction prevents phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy
Neuron, 2002Co-Authors: Masahisa Katsuno, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Hiroaki Adachi, Akito Kume, Hisayoshi Niwa, Chen Sang, Gen SobueAbstract:Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine disease caused by the expansion of a CAG repeat in the androgen receptor (AR) gene. We generated a transgenic mouse model carrying a full-length AR containing 97 CAGs. Three of the five lines showed progressive muscular atrophy and weakness as well as diffuse Nuclear staining and Nuclear Inclusions consisting of the mutant AR. These phenotypes were markedly pronounced in male transgenic mice, and dramatically rescued by castration. Female transgenic mice showed only a few manifestations that markedly deteriorated with testosterone administration. Nuclear translocation of the mutant AR by testosterone contributed to the phenotypic difference with gender and the effects of hormonal interventions. These results suggest the therapeutic potential of hormonal intervention for SBMA.
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Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine Nuclear Inclusions and neuronal dysfunction without neuronal cell death
Human molecular genetics, 2001Co-Authors: Hiroaki Adachi, Yuji Nakagomi, Yasushi Kobayashi, Manabu Doyu, Akito Kume, Hisayoshi Niwa, Chen Sang, SobueAbstract:We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ Nuclear Inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal Inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.
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Nonneural Nuclear Inclusions of androgen receptor protein in spinal and bulbar muscular atrophy
The American journal of pathology, 1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of AR-positive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions.
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Short Communication Nonneural Nuclear Inclusions of Androgen Receptor Protein in Spinal and Bulbar Muscular Atrophy
1998Co-Authors: Yuji Nakagomi, Kenneth H. Fischbeck, Yasushi Kobayashi, Dianne E. Merry, Fumiaki Tanaka, Manabu Doyu, Terunori Mitsuma, Yoshio Hashizume, SobueAbstract:Spinal and bulbar muscular atrophy is an X-linked motor neuronopathy caused by the expansion of an unstable CAG repeat in the coding region of the androgen receptor (AR) gene. Nuclear Inclusions of the mutant AR protein have been shown to occur in the spinal motor neurons of spinal and bulbar muscular atrophy (Li M, Kobayashi Y, Merry D, Tanaka F, Doyu M, Hashizume Y, Fischbeck KH, Sobue G: Nuclear Inclusions in spinal and bulbar muscular atrophy. Ann Neurol 1998 (in press)). In this study, we demonstrate the tissue-specific distribution, immunochemical features, and fine structure of Nuclear Inclusions of spinal and bulbar muscular atrophy. Nuclear Inclusions were observed in affected spinal and brainstem motor neurons, but not in other, nonaffected neural tissues. Similar Nuclear Inclusions occurred in nonneural tissues including scrotal skin, dermis, kidney, heart, and testis, but not in the spleen, liver, and muscle. These Inclusions had similar epitope features detectable by antibodies that recognize a small portion of the N-terminus of the AR protein only, and they were ubiquitinated. Electron microscopic immunohistochemistry showed dense aggregates of ARpositive granular material without limiting membrane, both in the neural and nonneural Inclusions. These findings indicate that Nuclear Inclusions of AR protein are present in selected nonneural tissues as well as in neurons that degenerate in spinal and bulbar muscular atrophy, suggesting that a common mechanism underlies in the formation of neural and nonneural Nuclear Inclusions. (Am J Pathol 1998, 153:695‐701)
Huda Y. Zoghbi - One of the best experts on this subject based on the ideXlab platform.
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neuronal dysfunction in a polyglutamine disease model occurs in the absence of ubiquitin proteasome system impairment and inversely correlates with the degree of Nuclear inclusion formation
Human Molecular Genetics, 2005Co-Authors: Aaron B Bowman, Nico P Dantuma, Huda Y. ZoghbiAbstract:The accumulation of protein deposits in neurons, in vitro proteasome assays and over-expression studies suggest that impairment of the ubiquitin–proteasome system (UPS) may be a common mechanism of pathogenesis in polyglutamine diseases such as Huntington disease and spinocerebellar ataxias (SCAs). Using a knock-in mouse model that recapitulates the clinical features of human SCA7, including selective neuronal dysfunction, we assessed the UPS at cellular resolution using transgenic mice that express a green fluorescent protein (GFP)-based reporter substrate (Ub G76V -GFP) of the UPS. The levels of the reporter remained low during the initial phase of disease, suggesting that neuronal dysfunction occurs in the presence of a functional UPS. Late in disease, we observed a significant increase in reporter levels specific to the most vulnerable neurons. Surprisingly, the basis for the increase in Ub G76V -GFP protein can be explained by a corresponding increase in Ub G76V -GFP mRNA in the vulnerable neurons. An in vitro assay also showed normal proteasome proteolytic activity in the vulnerable neurons. Thus, no evidence for general UPS impairment or reduction of proteasome activity was seen. The differential increase of Ub G76V -GFP among individual neurons directly correlated with the down-regulation of a marker of selective pathology and neuronal dysfunction in SCA7. Furthermore, we observed a striking inverse correlation between the neuropathology revealed by this reporter and ataxin-7 Nuclear Inclusions in the vulnerable neurons. Altogether, these data show a protective role against neuronal dysfunction for polyglutamine Nuclear Inclusions and exclude significant impairment of the UPS as a necessary step for polyglutamine neuropathology.
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SCA7 knockin mice model human SCA7 and reveal gradual accumulation of mutant ataxin-7 in neurons and abnormalities in short-term plasticity.
Neuron, 2003Co-Authors: Seung-yun Yoo, Shiming Chen, Mark E. Pennesi, Edwin J. Weeber, Richard Atkinson, Dawna L. Armstrong, J. David Sweatt, Huda Y. ZoghbiAbstract:We targeted 266 CAG repeats (a number that causes infantile-onset disease) into the mouse Sca7 locus to generate an authentic model of spinocerebellar ataxia type 7 (SCA7). These mice reproduced features of infantile SCA7 (ataxia, visual impairments, and premature death) and showed impaired short-term synaptic potentiation; downregulation of photoreceptor-specific genes, despite apparently normal CRX activity, led to shortening of photoreceptor outer segments. Wild-type ataxin-7 was barely detectable, as was mutant ataxin-7 in young animals; with increasing age, however, ataxin-7 staining became more pronounced. Neurons that appeared most vulnerable had relatively high levels of mutant ataxin-7; it is interesting, however, that marked dysfunction occurred in these neurons weeks prior to the appearance of Nuclear Inclusions. These data demonstrate that glutamine expansion stabilizes mutant ataxin-7, provide an explanation for selective neuronal vulnerability, and show that mutant ataxin-7 impairs posttetanic potentiation (PTP).
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Mutation of the E6-AP Ubiquitin Ligase Reduces Nuclear Inclusion Frequency While Accelerating Polyglutamine-Induced Pathology in SCA1 Mice
Neuron, 1999Co-Authors: Christopher J Cummings, Harry T Orr, Eyal Reinstein, Yaling Sun, Barbara Antalffy, Yong-hui Jiang, Aaron Ciechanover, Arthur L. Beaudet, Huda Y. ZoghbiAbstract:Mutant ataxin-1, the expanded polyglutamine protein causing spinocerebellar ataxia type 1 (SCA1), aggregates in ubiquitin-positive Nuclear Inclusions (NI) that alter proteasome distribution in affected SCA1 patient neurons. Here, we observed that ataxin-1 is degraded by the ubiquitin-proteasome pathway. While ataxin-1 [2Q] and mutant ataxin-1 [92Q] are polyubiquitinated equally well in vitro, the mutant form is three times more resistant to degradation. Inhibiting proteasomal degradation promotes ataxin-1 aggregation in transfected cells. And in mice, Purkinje cells that express mutant ataxin-1 but not a ubiquitin-protein ligase have significantly fewer NIs. Nonetheless, the Purkinje cell pathology is markedly worse than that of SCA1 mice. Taken together, NIs are not necessary to induce neurodegeneration, but impaired proteasomal degradation of mutant ataxin-1 may contribute to SCA1 pathogenesis.
