Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy

Katsuno, Masahisa; Adachi, Hiroaki; Doyu, Manabu; Minamiyama, Makoto; Sang, Chen; Kobayashi, Yasushi; Inukai, Akira; Sobue, Gen

doi:10.1038/nm878

Cited by 263 publications

(199 citation statements)

References 38 publications

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“…This is consistent with our previous result, showing that a reduction of HMGBs essential for architectural DNA alteration (Thomas and Travers, 2001) leads to genotoxic stress . It is also in line with previous findings that nuclear events largely initiate polyQ pathologies (Klement et al, 1998;Saudou et al, 1998;Katsuno et al, 2003).…”

Section: Discussionsupporting

confidence: 92%

“…Hoshino et al, 2006). The genotoxic stress hypothesis seems consistent with previous notions that nuclear events initiate the polyQ disease pathology (Klement et al, 1998;Saudou et al, 1998;Katsuno et al, 2003). Moreover, regarding cell death, activation of p53-p73 pathway leads to apoptosis in cultured cells (Bae et al, 2005) and to nonapoptotic, atypical cell death in primary neurons (Hoshino et al, 2006).…”

Section: Introductionsupporting

confidence: 82%

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Mutant huntingtin impairs Ku70-mediated DNA repair

Enokido¹,

Tamura²,

Ito³

et al. 2010

J Exp Med

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Section: Discussionsupporting

confidence: 92%

Section: Introductionsupporting

confidence: 82%

Mutant huntingtin impairs Ku70-mediated DNA repair

Enokido¹,

Tamura²,

Ito³

et al. 2010

J Exp Med

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“…In mice models therapy with GnRH analog Leuprorelin was tested, with evidence of reduction of nuclear inclusions [74]. Another approach consists in the use of 5α-reductase inhibitors, such as dutasteride.…”

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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“…The nuclei of the remaining neurons have abnormal protein deposits due to lengthened CAG repeats 7, 8. Androgen deprivation therapy using leuprorelin, a luteinizing hormone‐releasing hormone agonist, decreased abnormal protein deposits and attenuated neurodegeneration in a transgenic mouse model of SBMA 9. The potential effect of this therapy has also been suggested in clinical trials 10, 11…”

Section: Introductionmentioning

confidence: 99%

Swallowing markers in spinal and bulbar muscular atrophy

Banno

Katsuno

Suzuki

et al. 2017

Ann Clin Transl Neurol

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ObjectiveWe examined the characteristics of dysphagia in spinal and bulbar muscular atrophy, a hereditary neuromuscular disease causing weakness of limb, facial, and oropharyngeal muscles via a videofluoroscopic swallowing study, and investigated the plausibility of using these outcome measures for quantitative analysis.MethodsA videofluoroscopic swallowing study was performed on 111 consecutive patients with genetically confirmed spinal and bulbar muscular atrophy and 53 age‐ and sex‐matched healthy controls. Swallowing of 3‐mL liquid barium was analyzed by the Logemann's Videofluorographic Examination of Swallowing worksheet.ResultsOf more than 40 radiographic findings, the most pertinent abnormal findings in patients with spinal and bulbar muscular atrophy, included vallecular residue after swallow (residue just behind the tongue base), nasal penetration, and insufficient tongue movement (P < 0.001 for each) compared with healthy controls. Quantitative analyses showed that pharyngeal residue after initial swallowing, oral residue after initial swallowing, multiple swallowing sessions, and the penetration–aspiration scale were significantly worse in these patients (P ≤ 0.005 for each) than in controls. In patients with spinal and bulbar muscular atrophy, laryngeal penetration was observed more frequently in those without subjective dysphagia.InterpretationDysphagia of spinal and bulbar muscular atrophy was characterized by impaired tongue movement in the oral phase and nasal penetration followed by pharyngeal residues, which resulted in multiple swallowing sessions and laryngeal penetration. Although major limitations of reproducibility and radiation exposure still exist with videofluoroscopy, pharyngeal residue after initial swallowing and the penetration–aspiration scale might serve as potential outcome measures in clinical studies.

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Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy

Cited by 263 publications

References 38 publications

Mutant huntingtin impairs Ku70-mediated DNA repair

Mutant huntingtin impairs Ku70-mediated DNA repair

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

Swallowing markers in spinal and bulbar muscular atrophy

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