The Experts below are selected from a list of 2406 Experts worldwide ranked by ideXlab platform
Douglas A. Monks - One of the best experts on this subject based on the ideXlab platform.
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androgen receptor and Kennedy Disease spinal bulbar muscular atrophy
Hormones and Behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
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Androgen receptor and Kennedy Disease/spinal bulbar muscular atrophy,
Hormones and behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
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overexpression of wild type androgen receptor in muscle recapitulates polyglutamine Disease
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Douglas A. Monks, Andrew P. Lieberman, Jamie A. Johansen, Kaiguo Mo, Bryn Eagleson, Zhigang Yu, Marc S Breedlove, Cynthia L. JordanAbstract:We created transgenic mice that overexpress WT androgen receptor (AR) exclusively in their skeletal muscle fibers. Unexpectedly, these mice display androgen-dependent muscle weakness and early death, show changes in muscle morphology and gene expression consistent with neurogenic atrophy, and exhibit a loss of motor axons. These features reproduce those seen in models of Kennedy Disease, a polyglutamine expansion disorder caused by a CAG repeat expansion in the AR gene. These findings demonstrate that toxicity in skeletal muscles is sufficient to cause motoneuron Disease and indicate that overexpression of the WT AR can exert toxicity comparable with the polyglutamine expanded protein. This model has two clear implications for Kennedy Disease: (i) mechanisms affecting AR gene expression may cause neuromuscular symptoms similar to those of Kennedy Disease and (ii) therapeutic approaches targeting skeletal muscle may provide effective treatments for this Disease.
Annastiina Lund - One of the best experts on this subject based on the ideXlab platform.
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Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy Disease) around the world
European Journal of Human Genetics, 2001Co-Authors: Annastiina Lund, Vesa Juvonen, Bjarne Udd, Peter M Andersen, Kristina Cederquist, L O Ronnevi, Mark Davis, Cinzia Gellera, Christina Kölmel, Anne-dorte SperfeldAbstract:SBMA (spinal and bulbar muscular atrophy), also called Kennedy Disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their Disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide Diseases often show correlation between the repeat length and the severity and earlier onset of the Disease. The longer the repeat, the more severe the symptoms are and the onset of the Disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.
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Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.
European Journal of Human Genetics, 2000Co-Authors: Annastiina Lund, Vesa Juvonen, Pertti Sistonen, Bjarne Udd, Peter M Andersen, Kristina Cederquist, L O Ronnevi, Sven Asger Sørensen, Lisbeth Tranebjærg, Carina Wallgren-petterssonAbstract:We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy Disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.
Michael Q. Kemp - One of the best experts on this subject based on the ideXlab platform.
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androgen receptor and Kennedy Disease spinal bulbar muscular atrophy
Hormones and Behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
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Androgen receptor and Kennedy Disease/spinal bulbar muscular atrophy,
Hormones and behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
Andrew P. Lieberman - One of the best experts on this subject based on the ideXlab platform.
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microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy Disease spinal bulbar muscular atrophy
PLOS ONE, 2010Co-Authors: Zak Razak, Andrew P. Lieberman, Pengcheng Rao, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, Timothy J Westwood, Ashley D MonksAbstract:Background Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy Disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this Disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.
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altered rna splicing contributes to skeletal muscle pathology in Kennedy Disease knock in mice
Disease Models & Mechanisms, 2009Co-Authors: Adrienne M Wang, Diane M. Robins, Andrew P. LiebermanAbstract:Here, we used a mouse model of Kennedy Disease, a degenerative disorder caused by an expanded CAG repeat in the androgen receptor ( AR ) gene, to explore pathways leading to cellular dysfunction. We demonstrate that male mice containing a targeted Ar allele with 113 CAG repeats (AR113Q mice) exhibit hormone- and glutamine length-dependent missplicing of Clcn1 RNA in skeletal muscle. Changes in RNA splicing are associated with increased expression of the RNA-binding protein CUGBP1. Furthermore, we show that skeletal muscle denervation in the absence of a repeat expansion leads to increased CUGBP1 expression. However, this induction of CUGBP1 is not sufficient to alter Clcn1 RNA splicing, indicating that changes mediated by both denervation and AR113Q toxicity contribute to altered RNA processing. To test this notion directly, we exogenously expressed the AR in vitro and observed hormone-dependent changes in the splicing of pre-mRNAs from a human cardiac troponin T minigene. These effects were notably similar to changes mediated by RNA with expanded CUG tracts, but not CAG tracts, highlighting unanticipated similarities between CAG and CUG repeat Diseases. The expanded glutamine AR also altered hormone-dependent splicing of a calcitonin/calcitonin gene-related peptide minigene, suggesting that toxicity of the mutant protein additionally affects RNA processing pathways that are distinct from those regulated by CUGBP1. Our studies demonstrate the occurrence of hormone-dependent alterations in RNA splicing in Kennedy Disease models, and they indicate that these changes are mediated by both the cell-autonomous effects of the expanded glutamine AR protein and by alterations in skeletal muscle that are secondary to denervation.
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overexpression of wild type androgen receptor in muscle recapitulates polyglutamine Disease
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Douglas A. Monks, Andrew P. Lieberman, Jamie A. Johansen, Kaiguo Mo, Bryn Eagleson, Zhigang Yu, Marc S Breedlove, Cynthia L. JordanAbstract:We created transgenic mice that overexpress WT androgen receptor (AR) exclusively in their skeletal muscle fibers. Unexpectedly, these mice display androgen-dependent muscle weakness and early death, show changes in muscle morphology and gene expression consistent with neurogenic atrophy, and exhibit a loss of motor axons. These features reproduce those seen in models of Kennedy Disease, a polyglutamine expansion disorder caused by a CAG repeat expansion in the AR gene. These findings demonstrate that toxicity in skeletal muscles is sufficient to cause motoneuron Disease and indicate that overexpression of the WT AR can exert toxicity comparable with the polyglutamine expanded protein. This model has two clear implications for Kennedy Disease: (i) mechanisms affecting AR gene expression may cause neuromuscular symptoms similar to those of Kennedy Disease and (ii) therapeutic approaches targeting skeletal muscle may provide effective treatments for this Disease.
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Androgen-dependent pathology demonstrates myopathic contribution to the Kennedy Disease phenotype in a mouse knock-in model
The Journal of clinical investigation, 2006Co-Authors: Nahid Dadgar, Megan A. Albertelli, Kirsten L. Gruis, Cynthia L. Jordan, Diane M. Robins, Andrew P. LiebermanAbstract:Kennedy Disease, a degenerative disorder characterized by androgen-dependent neuromuscular weakness, is caused by a CAG/glutamine tract expansion in the androgen receptor (Ar) gene. We developed a mouse model of Kennedy Disease, using gene targeting to convert mouse androgen receptor (AR) to human sequence while introducing 113 glutamines. AR113Q mice developed hormone and glutamine length-dependent neuromuscular weakness characterized by the early occurrence of myopathic and neurogenic skeletal muscle pathology and by the late development of neuronal intranuclear inclusions in spinal neurons. AR113Q males unexpectedly died at 2-4 months. We show that this androgen-dependent death reflects decreased expression of skeletal muscle chloride channel 1 (CLCN1) and the skeletal muscle sodium channel alpha-subunit, resulting in myotonic discharges in skeletal muscle of the lower urinary tract. AR113Q limb muscles show similar myopathic features and express decreased levels of mRNAs encoding neurotrophin-4 and glial cell line-derived neurotrophic factor. These data define an important myopathic contribution to the Kennedy Disease phenotype and suggest a role for muscle in non-cell autonomous toxicity of lower motor neurons.
Pengcheng Rao - One of the best experts on this subject based on the ideXlab platform.
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microarray analysis of gene expression by skeletal muscle of three mouse models of Kennedy Disease spinal bulbar muscular atrophy
PLOS ONE, 2010Co-Authors: Zak Razak, Andrew P. Lieberman, Pengcheng Rao, Hiroaki Adachi, Masahisa Katsuno, Gen Sobue, Timothy J Westwood, Ashley D MonksAbstract:Background Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy Disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this Disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.
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androgen receptor and Kennedy Disease spinal bulbar muscular atrophy
Hormones and Behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
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Androgen receptor and Kennedy Disease/spinal bulbar muscular atrophy,
Hormones and behavior, 2008Co-Authors: Douglas A. Monks, Pengcheng Rao, Jamie A. Johansen, Gareth Lewis, Michael Q. KempAbstract:Kennedy Disease/Spinal Bulbar Muscular Atrophy (KD/SBMA) is a progressive neurodegenerative Disease caused by genetic polyglutamine expansion of the androgen receptor. We have recently found that overexpression of wildtype androgen receptor in skeletal muscle of transgenic mice results in a KD/SBMA phenotype. This surprising result challenges the orthodox view that KD/SBMA requires expression of polyglutamine expanded androgen receptor within motoneurons. Theories relating to the etiology of this Disease drawn from studies of human patients, cellular and mouse models are considered with a special emphasis on potential myogenic contributions to as well as the molecular etiology of KD/SBMA.
