Androgen-Dependent Neurodegeneration by Polyglutamine-Expanded Human Androgen Receptor in Drosophila

Takeyama, Ken Ichi; S, Itó; Yamamoto, Ayako; Tanimoto, Hiromu; Furutani, Takashi; Kanuka, Hirotaka; Miura, Masayuki; Tabata, Tetsuya; Kato, Shigeaki

doi:10.1016/s0896-6273(02)00875-9

Cited by 271 publications

(216 citation statements)

References 47 publications

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“…Flutamide has a very high affinity for AR and functions as an androgen antagonist by competing with testosterone for binding to AR. While flutamide suppresses the androgen-dependent transactivation activity of AR, it does not reduce plasma testosterone nor does it block nuclear translocation of mutant AR in either the mouse or Drosophila (Katsuno et al 2002(Katsuno et al , 2003Takeyama et al 2002). Thus, SBMA pathogenesis seems to be dependent on the translocation of mutant AR to the nucleus yet independent of ligand-induced activation of gene expression by AR.…”

Section: Sbma: Neurodegeneration Linked To a Nuclear Receptormentioning

confidence: 94%

“…In 2002, two reports appeared-one using a transgenic mouse model of SBMA (Katsuno et al 2002) and the other a Drosophila model (Takeyama et al 2002), in which the mutant phenotype was androgen dependent. In transgenic mice expressing intact AR with an ex- panded polyglutamine tract, only males developed motor neuron disease that was rescued by castration.…”

Section: Sbma: Neurodegeneration Linked To a Nuclear Receptormentioning

confidence: 99%

“…In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al 1998;Emamian et al 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al 2002(Katsuno et al , 2003Takeyama et al 2002).Central to the hypothesis of "host" protein amino acids having a fundamental role in pathogenesis is the concept that the normal function and protein interactions in which each polyglutamine-disease-associated protein participates are critical aspects of the pathogenic pathway. This review focuses on an examination of the evidence linking the disease-causing polyglutamine proteins to the regulation of transcription.…”

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Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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Section: Sbma: Neurodegeneration Linked To a Nuclear Receptormentioning

confidence: 94%

Section: Sbma: Neurodegeneration Linked To a Nuclear Receptormentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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“…Under normal conditions, upon binding of its ligands testosterone and dihydrotestosterone, AR is translocated from the cytosol into the nucleus, where it plays an important role in the regulation of gene expression. In SBMA, alteration of this pathway is retained to be a major pathogenic process [47] [48], associated with nuclear accumulation of the pathogenic protein [24], which may interfere with cellular functions. Nuclear inclusions and diffuse nuclear accumulation of polyQ-AR are histological markers of the disease and are found not only in motor neurons, but also in different regions of nervous system and in several non-neural cells (liver, cutis, kidney's proximal tubules, testis, prostate and scrotal skin) [24] [49] [25].…”

Section: Pathogenesismentioning

confidence: 99%

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

2017

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Acknowledgments: the authors thank AFM-Téléthon, Téléthon Biobank, Institut pour la Recherche sur la Moelle épinière et l'Encéphale (IRME), Association pour la Recherche sur la SLA (ARSla) and the University of Padova for their research support.Kennedy disease (X-Linked recessive Bulbospinal Neuronopathy): a comprehensive review from pathophysiology to therapy. AbstractKennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, Xlinked recessive neuromuscular disease. It is caused by expansion of a CAG repeat sequence in exon 1 of the androgen-receptor (AR) gene, encoding a poly-glutamine (polyQ) tract. Poly-Q-expanded AR accumulates in nuclei and initiates degeneration and loss of motor neurons and dorsal root ganglia. The disease has been retained to be a pure lower motor neuron disease for a long time, but recently the presence of important hyper-Creatine-Kinase-emia and of myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide proportion of clinical manifestations. The disease, that affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs and by bulbar involvement. Sensory disturbances are associated to the motor phenotype but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats retained to be pathogenic. Even though several therapeutic attempts have been made in mouse models, no effective disease modifying therapy is available but symptomatic therapy is beneficial for the management of weakness, fatigability and bulbar symptoms.

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Bulbospinal Muscular Atrophy

Sinnreich

Klein²

2004

Arch Neurol

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Androgen-Dependent Neurodegeneration by Polyglutamine-Expanded Human Androgen Receptor in Drosophila

Cited by 271 publications

References 47 publications

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy

Bulbospinal Muscular Atrophy

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