Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

Danek, Adrian; Witt, T. N.; Mann, Klaus; Schweikert, H. U.; Romalo, G.; Spada, Albert R. La; Fischbeck, Kenneth H.

doi:10.1007/bf00190748

Cited by 29 publications

(7 citation statements)

References 41 publications

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“…This androgen-dependent survival effect has implications for the pathogenesis of SBMA. Although the neuronal degeneration in this disease is due most likely to a toxic gain of function in the AR protein, the expanded-repeat AR is expressed at a level lower than that of the normal receptor in vivo and in vitro, resulting in a loss of function (Matsuura et al, i992;Danek et al, 1994;Warner et al, i992;Nakamura et al, i994;Brooks et al, 1997). As such, the motor neurons of SBMA patients may be less able to repair damage caused by the toxic gain-of-function.…”

Section: Figmentioning

confidence: 99%

A Cell Culture Model for Androgen Effects in Motor Neurons

Brooks¹,

Merry²,

Paulson³

et al. 1998

Journal of Neurochemistry

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Androgens are known to alter the morphology, survival, and axonal regeneration of lower motor neurons in vivo. To understand better the molecular mechanisms of androgen action in neurons, we created a model system by stably expressing the human androgen receptor (AR) in motor neuron hybrid cells. Motor neuron hybrid cells express markers consistent with anterior horn cells and can be differentiated into a neuronal phenotype. When differentiated in the presence of androgen, AR‐expressing cells, but not control cells, exhibit a dose‐dependent change in morphology: androgen‐treated cells develop larger cell bodies and broader neuritic processes while continuing to express neuronal markers. In addition, androgen promotes the survival of AR‐expressing cells, but not control cells, under low‐serum conditions. Our results demonstrate a direct trophic effect of androgens on lower motor neurons, mediated through the AR expressed in this population of neurons.

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Section: Figmentioning

confidence: 99%

A Cell Culture Model for Androgen Effects in Motor Neurons

Brooks¹,

Merry²,

Paulson³

et al. 1998

Journal of Neurochemistry

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“…Although the expansion of polyQ tract in AR deteriorates the transcriptional activities of AR (Mhatre et al, 1993;Brooks et al, 1997), motor impairment has not been observed in severe testicular feminization (Tfm) patients lacking AR function (Gottlieb et al, 1999). Thus, the neurologic impairment in SBMA cannot be attributed to the loss of AR function (Maclean et al, 1995), a reason why testosterone shows insufficient and transient effects when used as a therapeutic agent for SBMA (Danek et al, 1994;Goldenberg et al, 1996;Neuschmid-Kaspar et al, 1996). Animal models of Tfm demonstrate a decreased number of motor neurons in the spinal nucleus of the bulbocavernosus (Sengelaub et al, 1989) without any other motor neuron involvement.…”

Section: "Loss Of Function" Model Of Sbmamentioning

confidence: 99%

“…No specific treatment for SBMA has been established. Testosterone may improve motor function in some patients, although it has no effect on the progression of SBMA (Danek et al, 1994;Goldenberg et al, 1996;Neuschmid-Kaspar et al, 1996). The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyQ tract, in the first exon of the androgen receptor (AR) gene (La Spada et al, 1991).…”

Section: Spinal and Bulbar Muscular Atrophy (Sbma)mentioning

confidence: 99%

Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA)

Katsuno

Inukai

Sobue³

2003

Cytogenet Genome Res

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Spinal and bulbar muscular atrophy (SBMA) is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. Only males develop symptoms, while female carriers usually are asymptomatic. A specific treatment for SBMA has not been established. The molecular basis of SBMA is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine (polyQ) tract, in the first exon of the androgen receptor (AR) gene. The pathologic hallmark is nuclear inclusions (NIs) containing the mutant and truncated AR with expanded polyQ in the residual motor neurons in the brainstem and spinal cord as well as in some other visceral organs. Several transgenic (Tg) mouse models have been created for studying the pathogenesis of SBMA. The Tg mouse model carrying pure 239 CAGs under human AR promoter and another model carrying truncated AR with expanded CAGs show motor impairment and nuclear NIs in spinal motor neurons. Interestingly, Tg mice carrying full-length human AR with expanded polyQ demonstrate progressive motor impairment and neurogenic pathology as well as sexual difference of phenotypes. These models recapitulate the phenotypic expression observed in SBMA. The ligand-dependent nuclear localization of the mutant AR is found to be involved in the disease mechanism, and hormonal therapy is suggested to be a therapeutic approach applicable to SBMA.

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“…Abdominal obesity is common, whereas male pattern baldness is rare. Testosterone treatment has been administered to some patients, although it does not affect the progression of SBMA [13–15].…”

Section: Introductionmentioning

confidence: 99%

Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy

Adachi

Waza

Katsuno

et al. 2007

Neuropathology Appl Neurobio

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Spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease is a motor neurone disease characterized by muscle atrophy, weakness, contraction fasciculations and bulbar involvement. SBMA mainly affects males, while females are usually asymptomatic. SBMA is caused by expansion of a polyglutamine (polyQ)-encoding CAG trinucleotide repeat in the androgen receptor (AR) gene. AR belongs to the heat shock protein 90 (Hsp90) client protein family. The histopathologic hallmarks of SBMA are diffuse nuclear accumulation and nuclear inclusions of the mutant AR with expanded polyQ in residual motor neurones in the brainstem and spinal cord as well as in some other visceral organs. There is increasing evidence that the ligand of AR and molecular chaperones 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. In addition, elucidation of its pathophysiology using animal models has led to the development of disease-modifying drugs, that is, Hsp90 inhibitor and Hsp inducer, which inhibit the pathogenic process of neuronal degeneration. SBMA is a slowly progressive disease by nature. The degree of nuclear accumulation of mutant AR in scrotal skin epithelial cells was correlated with that in spinal motor neurones in autopsy specimens; therefore, the results of scrotal skin biopsy may be used to assess the efficacy of therapeutic trials. Clinical and pathological parameters that reflect the pathogenic process of SBMA should be extensively investigated.

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Decrease in androgen binding and effect of androgen treatment in a case of X-linked bulbospinal neuronopathy

Cited by 29 publications

References 41 publications

A Cell Culture Model for Androgen Effects in Motor Neurons

A Cell Culture Model for Androgen Effects in Motor Neurons

Transgenic mouse models of spinal and bulbar muscular atrophy (SBMA)

Pathogenesis and molecular targeted therapy of spinal and bulbar muscular atrophy

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