Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy

Iida, Madoka; Sahashi, Kentaro; Kondo, Naohide; Nakatsuji, Hideaki; Tohnai, Genki; Tsutsumi, Yutaka; Noda, Seiya; Murakami, Ayuka; Onodera, Kazunari; Okada, Yohei; Nakatochi, Masahiro; Okabe, Yuka Tsukagoshi; Shimizu, Shinobu; Mizuno, Masaaki; Sobue, Gen; Katsuno, Masahisa

doi:10.1038/s41467-019-12282-7

Cited by 16 publications

(18 citation statements)

References 70 publications

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“…For instance, the pathogenic AR with elongated polyglutamine activates Src, a non-receptor protein tyrosine kinase, both in the spinal cord and skeletal muscle of AR-97Q mouse. 32 An Src inhibitor ameliorates the neuromuscular phenotype of SBMA by mitigating Src-dependent activation of p130Cas, without suppressing the nuclear accumulation of the pathogenic AR. In addition, the polyglutamine-expanded AR causes epigenetic dysregulation such as histone deacetylation and DNA hyper methylation in neurons.…”

Section: Androgen-dependent Disease Mechanismmentioning

confidence: 99%

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Hashizume

Fischbeck

Pennuto

et al. 2020

J Neurol Neurosurg Psychiatry

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Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

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Section: Androgen-dependent Disease Mechanismmentioning

confidence: 99%

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Hashizume

Fischbeck

Pennuto

et al. 2020

J Neurol Neurosurg Psychiatry

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“…In addition to gene level dysregulation, alteration of signaling pathways also occurs at the protein level. Using phosphorylation protein arrays from spinal cord and skeletal muscle from mice that were pre-onset, early manifesting, and at advanced stages of disease, changes in the Src signaling pathway were detected in both tissues at all time points evaluated [22]. Treatment of SBMA cells and mice with inhibitors of Src signaling resulted in improved cellular viability, and body weight and grip strength in animals treated at 8 weeks of age.…”

Section: Disrupted Signaling Pathwaysmentioning

confidence: 99%

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

Fischbeck

2020

Current Opinion in Neurology

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Purpose of review:To illustrate the current understanding and avenues for developing treatment in spinal and bulbar muscular atrophy (SBMA), an inherited neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor (AR) gene.Recent findings: Important advances have been made in characterizing the molecular mechanism of the disease including the disruption of protein homeostasis, intracellular trafficking, and signaling pathways. Biomarkers such as MRI quantification of muscle volume and fat fraction have been used to track disease progression, and will be useful in future clinical studies. Therapies tested and under development have been based on diverse strategies including targeting mutant AR gene expression, stability, and activity, and pathways that mitigate disease toxicity. Summary:We provide an overview of the recent advances in understanding the SBMA disease mechanism and highlight efforts to translate these insights into safe and effective therapy.

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“…To further investigate the involvement of Src signaling in the action of NECTIN4, Src was reactivated in the NECTIN4 siRNA-transfected cells and cell proliferation and angiogenesis was assessed. MLR-1023 was used as an activator, which is reported to induce phosphorylation of Src 30 . When NECTIN4 siRNA-transfected cells were further treated with MLR-1023, the number of live cells was significantly increased compared with NECTIN4 siRNA-transfected, DMSO-treated cells in both HAMON and ISO-HAS-B (Fig.…”

Section: Resultsmentioning

confidence: 99%

Nectin cell adhesion molecule 4 regulates angiogenesis through Src signaling and serves as a novel therapeutic target in angiosarcoma

Tanaka

Murata

Tanegashima

et al. 2022

Sci Rep

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Angiosarcoma is a rare, life-threatening soft tissue sarcoma with malignant endothelial cells that is mainly found in the skin. Multidisciplinary approaches are used to treat patients with unresectable metastasized lesions; considering the cellular origin of angiosarcoma, anti-angiogenic therapy has also been used recently. However, these treatments have limited efficacy, and the survival rate remains low. Thus, more effective treatments need to be developed. Nectin cell adhesion molecule 4 (NECTIN4) is highly expressed in malignant tumors and promotes tumor progression. Thus, NECTIN4 is expected to be a novel therapeutic target for cancer. However, the significance of NECTIN4 in angiosarcoma remains unknown. Using immunohistochemistry, we investigated NECTIN4 expression in 74 tissue samples from angiosarcoma patients, finding variable NECTIN4 expression. In addition, we investigated NECTIN4 expression and function in human angiosarcoma cell lines. NECTIN4 expression was higher in angiosarcoma cells than normal endothelial cells, and angiosarcoma cells were sensitive to monomethyl auristatin E, the cytotoxic part of a NECTIN4-targetting antibody–drug conjugate. NECTIN4 knockdown inhibited the proliferation and angiogenesis of angiosarcoma cells, and Src kinase signaling was shown to be involved in NECTIN4 function, at least in part. NECTIN4-targeted therapy has the potential to be a novel treatment strategy for angiosarcoma.

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Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy

Cited by 16 publications

References 70 publications

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Molecular pathogenesis of spinal bulbar muscular atrophy (Kennedy's disease) and avenues for treatment

Nectin cell adhesion molecule 4 regulates angiogenesis through Src signaling and serves as a novel therapeutic target in angiosarcoma

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