Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy

Thomas, Patrick S.; Fraley, Gregory S.; Damian, Vincent; Woodke, Lillie B.; Zapata, Francisco; Sopher, Bryce L.; Plymate, Stephen R.; Spada, Albert R. La

doi:10.1093/hmg/ddl226

Cited by 19 publications

(22 citation statements)

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“…Indeed, SBMA patients present frequently with symptoms of partial androgen insensitivity, such as gynecomastia, reduced libido and impotence (Querin et al, 2015). Moreover, loss of endogenous AR has been shown to aggravate the phenotype caused by mutant AR, thereby showing a contribution of the loss of AR function in SBMA (Thomas et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?

Pennuto

Rinaldi

2018

Molecular and Cellular Endocrinology

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Abnormal polyglutamine expansions in the androgen receptor (AR) cause a muscular condition, known as Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). The disease is transmitted in an X-linked fashion and is clinically characterized by weakness, atrophy and fasciculations of the limb and bulbar muscles as a result of a toxic gain-of-function of the mutant protein. Notably, affected males also show signs of androgen insensitivity, such as gynaecomastia and reduced fertility. The characterization of the natural history of the disease, the increasing understanding of the mechanism of pathogenesis and the elucidation of the functions of normal and mutant AR have offered a momentum for developing a rational therapeutic strategy for this disease. In this special issue on androgens and AR functions, we will review the molecular, biochemical, and cellular mechanisms underlying the pathogenesis of SBMA. We will discuss recent advances on therapeutic approaches and opportunities for this yet incurable disease, ranging from androgen deprivation, to gene silencing, to an expanding repertoire of peripheral targets, including muscle. With the advancement of these strategies into the clinic, it can be reasonably anticipated that the landscape of treatment options for SBMA and other neuromuscular conditions will change rapidly in the near future.

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Section: Introductionmentioning

confidence: 99%

From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?

Pennuto

Rinaldi

2018

Molecular and Cellular Endocrinology

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“…Expansion of polyglutamine confers a toxic gain of function on the mutant protein. Evidence also indicates a contribution of loss of protein function to the disease pathogenesis (Zuccato et al, 2001; Thomas et al, 2006; Lim et al, 2008). Although disease‐specific features imply the contribution of protein‐specific features in polyglutamine disease pathogenesis, the observation that the same mutation in nine unrelated genes causes neurodegeneration suggests a common disease mechanism.…”

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confidence: 99%

B2 attenuates polyglutamine‐expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy

Palazzolo

Nedelsky

Askew

et al. 2010

J of Neuroscience Research

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Expanded polyglutamine tracts cause neurodegeneration through a toxic gain of function mechanism. Generation of inclusions is a common feature of polyglutamine diseases and other protein misfolding disorders. Inclusion formation is likely to be a defensive response of the cell to the presence of unfolded protein. Recently, the compound B2 has been shown to increase inclusion formation and decrease toxicity of polyglutamine-expanded huntingtin in cultured cells. We explored the effect of B2 on spinal and bulbar muscular atrophy (SBMA). SBMA is caused by expansion of polyglutamine in the androgen receptor (AR) and is characterized by the loss of motor neurons in the brainstem and spinal cord. We found that B2 increases the deposition of mutant AR into nuclear inclusions without altering the ligand-induced aggregation, expression, or subcellular distribution of the mutant protein. The effect of B2 on inclusions was associated with a decrease in AR transactivation function. Importantly, we show that B2 reduces mutant AR toxicity in cell and fly models of SBMA, further supporting the idea that accumulation of polyglutamine-expanded protein into inclusions is protective. Our findings suggest B2 as a novel approach to therapy for SBMA.

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“…Recent studies have indicated that mutations in several dominantly inherited diseases, including polyglutamine diseases, prion disease, and Alzheimer's disease, contributed to pathology through both a loss-and gainof-function (Van Raamsdonk et al, 2005;Harris and True, 2006;Thomas et al, 2006;Shen and Kelleher, 2007;Lim et al, 2008). For example, in the case of spinocerebellar ataxia type 1, which is one of the polyglutamine diseases and caused by the expansion of a glutamine-encoding CAG repeat in the ataxin-1 gene, ataxin-1 protein forms at least two distinct native complexes.…”

Section: Discussionmentioning

confidence: 99%

In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele

et al. 2011

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Gene therapy for dominantly inherited diseases with small interfering RNA (siRNA) requires mutant allele-specific suppression when genes in which mutation causes disease normally have an important role. We previously proposed a strategy for selective suppression of mutant alleles; both mutant and wild-type alleles are inhibited by most effective siRNA, and wild-type protein is restored using mRNA mutated to be resistant to the siRNA. Here, to prove the principle of this strategy in vivo, we applied it to our previously reported anti-copper/zinc superoxide dismutase (SOD1) short hairpin RNA (shRNA) transgenic (Tg) mice, in which the expression of the endogenous wild-type SOD1 gene was inhibited by more than 80%. These shRNA Tg mice showed hepatic lipid accumulation with mild liver dysfunction due to downregulation of endogenous wild-type SOD1. To rescue this side effect, we generated siRNA-resistant SOD1 Tg mice and crossed them with anti-SOD1 shRNA Tg mice, resulting in the disappearance of lipid accumulation in the liver. Furthermore, we also succeeded in mutant SOD1-specific gene suppression in the liver of SOD1(G93A) Tg mice, a model for amyotrophic lateral sclerosis, using intravenously administered viral vectors. Our method may prove useful for siRNA-based gene therapy for dominantly inherited diseases.

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Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy

Cited by 19 publications

References 0 publications

From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?

From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?

B2 attenuates polyglutamine‐expanded androgen receptor toxicity in cell and fly models of spinal and bulbar muscular atrophy

In Vivo Application of an RNAi Strategy for the Selective Suppression of a Mutant Allele

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