Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration
Reversible disruption of dynactin 1-mediated retrograde axonal transport in polyglutamine-induced motor neuron degeneration
复制标题
DOI：
10.1523/jneurosci.3032-06.2006
复制
发表时间：
2006-11-22
影响因子：
5.3
通讯作者：
Sobue, Gen
中科院分区：
文献类型：
--
作者：
Katsuno, Masahisa;Adachi, Hiroaki;Sobue, Gen
脊髓延髓肌萎缩症（SBMA）是一种遗传性神经退行性疾病，由雄激素受体（AR）基因中编码多聚谷氨酰胺序列的三核苷酸CAG重复序列扩增引起。为了阐明多聚谷氨酰胺介导的运动神经元功能障碍的发病机制，我们研究了携带人类致病性AR的SBMA转基因小鼠模型的组织病理学和生物学改变。在受影响的小鼠中，神经丝和突触素积聚在远端运动轴突。在SBMA患者的骨骼肌中检测到类似的神经丝肌内积聚。荧光金标记和坐骨神经结扎表明，在转基因小鼠逆行轴突运输受损。在SBMA小鼠中，由于致病性AR诱导的转录失调，dynactin 1（一种用于逆行运输的轴突马达）的mRNA水平显著降低。这些病理学事件在神经系统症状发作之前观察到，但通过去势逆转，这防止了致病性AR的核积聚。在SBMA的细胞培养模型中，dynactin 1的过表达减轻了致病性AR的神经元毒性。这些观察结果表明，多聚谷氨酰胺依赖的dynactin 1的转录失调在SBMA早期可逆的神经元功能障碍中起着至关重要的作用。
Spinal and bulbar muscular atrophy (SBMA) is a hereditary neurodegenerative disease caused by an expansion of a trinucleotide CAG repeat encoding the polyglutamine tract in the androgen receptor (AR) gene. To elucidate the pathogenesis of polyglutamine-mediated motor neuron dysfunction, we investigated histopathological and biological alterations in a transgenic mouse model of SBMA carrying human pathogenic AR. In affected mice, neurofilaments and synaptophysin accumulated at the distal motor axon. A similar intramuscular accumulation of neurofilament was detected in the skeletal muscle of SBMA patients. Fluoro-gold labeling and sciatic nerve ligation demonstrated an impaired retrograde axonal transport in the transgenic mice. The mRNA level of dynactin 1, an axon motor for retrograde transport, was significantly reduced in the SBMA mice resulting from pathogenic AR-induced transcriptional dysregulation. These pathological events were observed before the onset of neurological symptoms, but were reversed by castration, which prevents nuclear accumulation of pathogenic AR. Overexpression of dynactin 1 mitigated neuronal toxicity of the pathogenic AR in a cell culture model of SBMA. These observations indicate that polyglutamine-dependent transcriptional dysregulation of dynactin 1 plays a crucial role in the reversible neuronal dysfunction in the early stage of SBMA.