Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein

Adachi, Hiroaki; Katsuno, Masahisa; Minamiyama, Makoto; Sang, Chen; Pagoulatos, Gerassimos N.; Angelidis, Charalampos; Kusakabe, Moriaki; Yoshiki, Atsushi; Kobayashi, Yasushi; Doyu, Manabu; Sobue, Gen

doi:10.1523/jneurosci.23-06-02203.2003

Cited by 239 publications

(150 citation statements)

References 59 publications

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“…The fact that AR has a specific ligand (i.e., testosterone), renders the pathogenesis of SBMA unique among polyQ diseases (Poletti et al, 2005). There is increasing evidence that the AR ligand Chevalier-Larsen et al, 2004;Sopher et al, 2004;Katsuno et al, 2006;Yu et al, 2006) and molecular chaperones (Kobayashi et al, 2000;Bailey et al, 2002;Adachi et al, 2003) play a crucial role in the pathogenesis of SBMA. The success of androgen deprivation therapy in SBMA mouse models has been translated into clinical trials .…”

Section: Discussionmentioning

confidence: 99%

“…These results suggest that chaperone interaction is essential for CHIP-dependent ubiquitination. Hsp70 overexpression in cell culture and mouse models of SBMA enhanced degradation of mutant AR-polyQ protein via its interaction with the ubiquitin-proteasome system (Bailey et al, 2002;Adachi et al, 2003). CHIP might be one such coupling factor between the Hsp70 chaperone system and the machinery responsible for degrading mutant AR.…”

Section: Discussionmentioning

confidence: 99%

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CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Adachi¹,

Waza²,

Tokui³

et al. 2007

J. Neurosci.

133

143

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Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor (AR). The pathologic features of SBMA are motor neuron loss in the spinal cord and brainstem and diffuse nuclear accumulation and nuclear inclusions of the mutant AR in the residual motor neurons and certain visceral organs. Many components of the ubiquitin-proteasome and molecular chaperones are also sequestered in the inclusions, suggesting that they may be actively engaged in an attempt to degrade or refold the mutant AR. C terminus of Hsc70 (heat shock cognate protein 70)-interacting protein (CHIP), a U-box type E3 ubiquitin ligase, has been shown to interact with heat shock protein 90 (Hsp90) or Hsp70 and ubiquitylates unfolded proteins trapped by molecular chaperones and degrades them. Here, we demonstrate that transient overexpression of CHIP in a neuronal cell model reduces the monomeric mutant AR more effectively than it does the wild type, suggesting that the mutant AR is more sensitive to CHIP than is the wild type. High expression of CHIP in an SBMA transgenic mouse model also ameliorated motor symptoms and inhibited neuronal nuclear accumulation of the mutant AR. When CHIP was overexpressed in transgenic SBMA mice, mutant AR was also preferentially degraded over wild-type AR. These findings suggest that CHIP overexpression ameliorates SBMA phenotypes in mice by reducing nuclear-localized mutant AR via enhanced mutant AR degradation. Thus, CHIP overexpression would provide a potential therapeutic avenue for SBMA.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Adachi¹,

Waza²,

Tokui³

et al. 2007

J. Neurosci.

133

143

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“…In general, the misfolding and aggregation of proteins are prevented by molecular chaperones (23,24). Some molecular chaperones such as heat shock protein (Hsp) 70 and Hsp40 have recently been identified as important regulators of polyglutamine aggregation and/or cell death in in vitro assays (25), in cultured mammalian cells (26 -31), in a Drosophila model (32) and in transgenic mice (33,34). Hsp27 was also identified as a suppressor of polyglutamine-mediated cell death using a cellular model of Huntington's disease (35).…”

mentioning

confidence: 99%

Hsp105α Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity

Ishihara

Yamagishi

Saito

et al. 2003

Journal of Biological Chemistry

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Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disorder caused by the expansion of a polyglutamine tract in the androgen receptor (AR). The N-terminal fragment of AR containing the expanded polyglutamine tract aggregates in cytoplasm and/or in nucleus and induces cell death. Some chaperones such as Hsp40 and Hsp70 have been identified as important regulators of polyglutamine aggregation and/or cell death in neuronal cells. Recently, Hsp105␣, expressed at especially high levels in mammalian brain, has been shown to suppress apoptosis in neuronal cells and prevent the aggregation of protein caused by heat shock in vitro. However, its role in polyglutamine-mediated cell death and toxicity has not been studied. In the present study, we examined the effects of Hsp105␣ on the aggregation and cell toxicity caused by expansion of the polyglutamine tract using a cellular model of SBMA. The transient expression of truncated ARs (tARs) containing an expanded polyglutamine tract caused aggregates to form in COS-7 and SK-N-SH cells and concomitantly apoptosis in the cells with the nuclear aggregates. When Hsp105␣ was overexpressed with tAR97 in the cells, Hsp105␣ was colocalized to aggregates of tAR97, and the aggregation and cell toxicity caused by expansion of the polyglutamine tract were markedly reduced. Both ␤-sheet and ␣-helix domains, but not the ATPase domain, of Hsp105␣ were necessary to suppress the formation of aggregates in vivo and in vitro. Furthermore, Hsp105␣ was found to localize in nuclear inclusions formed by ARs containing an expanded polyglutamine tract in tissues of patients and transgenic mice with SBMA. These findings suggest that overexpression of Hsp105␣ suppresses cell death caused by expansion of the polyglutamine tract without chaperone activity, and the enhanced expression of the essential domains of Hsp105␣ in brain may provide an effective therapeutic approach for CAG repeat diseases.

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“…Overexpression of Hsp70 and Hsp40 has been shown to reduce AR aggregation and toxicity in mouse models [83] [84] [85]. Moreover, using Hsp inhibitors [86] or co-inducers of the HSR mediated by the transcription factor heat shock factor 1 (HSF1) [87] expression levels of Hsps can be enhanced.…”

Section: Experimental Treatmentsmentioning

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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Heat Shock Protein 70 Chaperone Overexpression Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model by Reducing Nuclear-Localized Mutant Androgen Receptor Protein

Cited by 239 publications

References 59 publications

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

CHIP Overexpression Reduces Mutant Androgen Receptor Protein and Ameliorates Phenotypes of the Spinal and Bulbar Muscular Atrophy Transgenic Mouse Model

Hsp105α Suppresses the Aggregation of Truncated Androgen Receptor with Expanded CAG Repeats and Cell Toxicity

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

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