Development of Pathogenesis-based treatment for spinal and bulbar muscular atrophy

脊髓和延髓性肌萎缩症基于发病机制的治疗方法的开发

• 批准号: 15209031
• 负责人: SOBUE Gen
• 金额: $ 32.28万
• 依托单位: Nagoya University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-15209031/
• 关键词: Neurodegeneration; motor neuron; polyglutamine; androgen receptor; histone; heat shock protein; geranylgeranylaceone; テストステロン; LHRHアナログ; フルタミド; HSP

Spinal and bulbar muscular atrophy(SBMA), a hereditary motor neuron disease affecting adult males, is caused by expansion of CAG trinucleotide repeat in the androgen receptor(AR) gene. Histopathological analysis of the spinal cord from SBMA patients demonstrated that the extent of diffuse nuclear accumulation of mutant AR in motor and sensory neurons of the spinal cord was closely related to CAG repeat length. A transgenic mouse model of SBMA carrying full-length human AR gene containing 97 CAGs showed significant sexual differences in phenotypes which was more progressive in males than females. Testosterone deprivation with either surgical castration or LHRH analogue treatment suppressed nuclear accumulation of mutant AR protein and thereby significantly improved neurological phenotypes and histopathological abnormalities in SBMA mice. Clinical trial of LHRH analogue for SBMA patients is currently being conducted.Cross-breeding of SBMA transgenic mice with mice overexpressing human Hsp70 resulted in inhibition of nuclear accumulation of mutant AR as well as marked amelioration of the motor function. Hsp70 did not only inhibit aggregation of mutant AR but also facilitated degradation of this protein. In a cell culture model of SBMA, geranylgeranylacetone, Hsp70 inducer enhanced suppressed nuclear accumulation of mutant AR, resulting in mitigation of neurotoxicity exerted by expanded polyglutamine. Oral administration of GGA also alleviated neuronal dysfunction in SBMA mice.Oral administration of sodium butyrate, a histone deacetylase inhibitor, upregulated histone acetylation and ameliorated phenotypes of SBMA mice, although therapeutic window of sodium butyrate was narrow.Our results suggest that inhibition of nuclear AR accumulation, enhancement of AR degradation, and restoration of transcription are the targets in pathogenesis-based therapeutic strategies for SBMA. (266 words)

脊髓和延髓肌萎缩症(SBMA)是一种影响成年男性的遗传性运动神经元疾病，由雄激素受体(AR)基因中CAG三核苷酸重复序列的扩增引起。对SBMA患者脊髓的组织病理学分析表明，突变型AR在脊髓运动神经元和感觉神经元的弥漫性核积聚程度与CAG重复长度密切相关。携带含有97个CAG的全长人AR基因的SBMA转基因小鼠模型在表型上显示出显着的性别差异，男性比女性更进步。手术去势或LHRH类似物治疗的睾丸激素剥夺抑制了突变AR蛋白的核积聚，从而显着改善了SBMA小鼠的神经学表型和组织病理学异常。针对SBMA患者的LHRH类似物目前正在进行临床试验。SBMA转基因小鼠与高表达人Hsp70的小鼠杂交，可抑制突变型AR的核积聚，并显著改善运动功能。HSP70不仅抑制了突变型AR的聚集，而且促进了该蛋白的降解。在SBMA细胞培养模型中，香叶基香叶内酮、Hsp70诱导剂增强抑制了突变型AR的核聚集，从而减轻了膨化聚谷氨酰胺的神经毒性。口服GGA也可减轻SBMA小鼠的神经元功能障碍。尽管丁酸钠的治疗窗口较窄，但口服丁酸钠可上调组蛋白乙酰化并改善SBMA小鼠组蛋白乙酰化和表型。我们的结果表明，抑制核AR积聚、促进AR降解和恢复转录是SBMA发病机制治疗策略的靶点。(266字)

项目成果

Dorfin prevents cell death by reducing mitochondrial localising mutant superoxide dismutase 1 in a neuronal cell model of familial amyotrophic lateral sclerosis.

在家族性肌萎缩侧索硬化症神经元细胞模型中，Dorfin 通过减少线粒体定位突变型超氧化物歧化酶 1 来防止细胞死亡。

• 发表时间: 2004
• 期刊: J Neurochem 89
• 作者: Takeuchi H;Niwa J;Hishikawa N;Ishigaki S;Tanaka F;Doyu M;Sobue G
• 通讯作者: Sobue G

Gene expression profile of spinal motor neurons in sporadic amyotrophic lateral sclerosis

• DOI: 10.1002/ana.20379
• 发表时间: 2005-02-01
• 期刊: ANNALS OF NEUROLOGY
• 影响因子: 11.2
• 作者: Jiang, YM;Yamamoto, M;Sobue, G
• 通讯作者: Sobue, G

Occipital hypoperfusion in Parkinson's disease without dementia: correlation to impaired cortical visual processing

• DOI: 10.1136/jnnp.74.4.419
• 发表时间: 2003-04-01
• 期刊: JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY
• 影响因子: 11
• 作者: Abe, Y;Kachi, T;Sobue, G
• 通讯作者: Sobue, G

Multiple regional 1H-MR spectroscopy in multiple system atrophy : NAA/Cr reduction in pontine base as a valuable diagnostic marker

多系统萎缩中的多区域 1H-MR 光谱：脑桥基部 NAA/Cr 减少作为有价值的诊断标志物

• 发表时间: 2004
• 期刊: J Neurol Neurosurg Psychiatry 75
• 作者: Adachi H;Katsuno M;Minamiyama M;Sang C;Nakagomi Y;Kobayashi Y;Tanaka F;Doyu M;Inukai A;Yoshida M;Hashizume Y;Sobue G;Jiang YM;Watanabe H
• 通讯作者: Watanabe H

Onset age and severity impairment are associated with reduction of myocardial ^<123>I-MIBG uptake in Parkinson's disease

帕金森病的发病年龄和严重程度损害与心肌^ 123 I-MIBG摄取减少相关

• 发表时间: 2003
• 期刊: J Neurol Neurosurg Psychiatry 74(4)
• 作者: Okada Y;Shimazaki T;Sobue G;Okano H;Katsuno M;Katsuno M;Yamada S;Minamiyama M;Mitsuma N;Okada Y;Hattori N;Hishikawa N;Hamada K
• 通讯作者: Hamada K