Grunseich Christopher, Zukosky Kristen, Kats Ilona R, Ghosh Laboni, Harmison George G, Bott Laura C, Rinaldi Carlo, Chen Ke-lian, Chen Guibin, Boehm Manfred, Fischbeck Kenneth H
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA.
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, 2A-1000 Building 35, 35 Convent Drive, NIH, Bethesda, MD 20892, USA; Department of Cell and Molecular Biology, Karolinska Institute, Solnavagen 1, 17177 Solna, Sweden.
Neurobiol Dis. 2014 Oct;70:12-20. doi: 10.1016/j.nbd.2014.05.038. Epub 2014 Jun 9.
Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy.
脊髓延髓肌肉萎缩症（SBMA，肯尼迪病）是一种由雄激素受体中多聚谷氨酰胺重复序列扩增引起的运动神经元疾病。尽管脊髓和肌肉会发生退化，但其确切机制尚不清楚。脊髓延髓肌肉萎缩症患者的诱导多能干细胞为理解疾病机制和设计有效治疗方法提供了有用的模型。从6名患者中生成了干细胞，并与3名健康个体的对照细胞系进行比较。从4名患者的干细胞中分化出运动神经元，并对其进行表征以了解与疾病相关的表型。由患者成纤维细胞产生的干细胞表达的雄激素受体比对照细胞少，但显示出雄激素依赖性的稳定和核转位。几个干细胞克隆中的扩增重复序列不稳定，存在扩增或收缩现象。与对照组相比，无论有无雄激素处理，患者干细胞克隆产生的运动神经元数量相似。干细胞衍生的运动神经元对HB9、Isl1、ChAT和SMI-32具有免疫反应性，并且发现重复序列扩增最大的那些运动神经元乙酰化α-微管蛋白增加而HDAC6减少。在另外两名重复序列较短的患者的运动神经元培养物中也发现了HDAC6减少。对稳定转染的小鼠细胞和SBMA脊髓的评估显示乙酰化α-微管蛋白和HDAC6有类似变化。核周溶酶体富集是一个依赖HDAC6的过程，在两名重复序列最长的患者的运动神经元中被破坏。SBMA干细胞为该疾病提供了新的见解，雄激素受体水平降低、重复序列不稳定和HDAC6减少的观察结果为进一步研究疾病机制和开发有效治疗方法提供了途径。
