Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA).
Skeletal muscle DNA damage precedes spinal motor neuron DNA damage in a mouse model of Spinal Muscular Atrophy (SMA).
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DOI：
10.1371/journal.pone.0093329
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Martin LJ
中科院分区：
文献类型：
--
作者：
Fayzullina S;Martin LJ
脊髓性肌萎缩症（SMA）是一种遗传性儿童疾病，通过骨骼肌和脊髓运动神经元的进行性变性导致瘫痪。SMA与全长运动神经元存活（SMN）蛋白水平降低相关，这是由于运动神经元存活1基因突变所致。缺乏SMN导致SMA病理学的机制尚不清楚，因此很难开发有效的治疗方法。我们研究了DNA损伤是否是SMA的围产期病理事件，以及DNA损伤和细胞死亡是否首先发生在SMA小鼠的骨骼肌或脊髓中。我们使用严重SMA的小鼠模型来确定产前和新生小鼠全身细胞死亡和DNA损伤的程度。SMA小鼠出生时（出生后第0天）后肢骨骼肌的基因组DNA出现核小体间断裂，但脊髓的基因组DNA未出现核小体间断裂。SMA小鼠在出生后第5天，与同窝对照组相比，表现出增加的骨骼肌细胞凋亡，苏木精和伊红，末端脱氧核苷酸转移酶dUTP缺口末端标记，和电子显微镜。SMA小鼠没有增加细胞死亡，没有胆碱乙酰转移酶（ChAT）阳性运动神经元的损失，脊髓腹角没有明显的病理学。在胚胎第13天和第15.5天，SMA小鼠脊髓或骨骼肌中的细胞死亡特征未表现出统计学显著性增加。在腹角的运动神经元数量，确定的ChAT免疫反应，SMA小鼠和对照同窝仔在胚胎第15.5天和出生后第5天。这些观察结果表明，在SMA中，骨骼肌疾病先于脊髓病理学出现，包括运动神经元丢失。总体而言，这项工作确定了骨骼肌中的DNA损伤和细胞死亡作为SMA的治疗靶点。
Spinal Muscular Atrophy (SMA) is a hereditary childhood disease that causes paralysis by progressive degeneration of skeletal muscles and spinal motor neurons. SMA is associated with reduced levels of full-length Survival of Motor Neuron (SMN) protein, due to mutations in the Survival of Motor Neuron 1 gene. The mechanisms by which lack of SMN causes SMA pathology are not known, making it very difficult to develop effective therapies. We investigated whether DNA damage is a perinatal pathological event in SMA, and whether DNA damage and cell death first occur in skeletal muscle or spinal cord of SMA mice. We used a mouse model of severe SMA to ascertain the extent of cell death and DNA damage throughout the body of prenatal and newborn mice. SMA mice at birth (postnatal day 0) exhibited internucleosomal fragmentation in genomic DNA from hindlimb skeletal muscle, but not in genomic DNA from spinal cord. SMA mice at postnatal day 5, compared with littermate controls, exhibited increased apoptotic cell death profiles in skeletal muscle, by hematoxylin and eosin, terminal deoxynucleotidyl transferase dUTP nick end labeling, and electron microscopy. SMA mice had no increased cell death, no loss of choline acetyl transferase (ChAT)-positive motor neurons, and no overt pathology in the ventral horn of the spinal cord. At embryonic days 13 and 15.5, SMA mice did not exhibit statistically significant increases in cell death profiles in spinal cord or skeletal muscle. Motor neuron numbers in the ventral horn, as identified by ChAT immunoreactivity, were comparable in SMA mice and control littermates at embryonic day 15.5 and postnatal day 5. These observations demonstrate that in SMA, disease in skeletal muscle emerges before pathology in spinal cord, including loss of motor neurons. Overall, this work identifies DNA damage and cell death in skeletal muscle as therapeutic targets for SMA.
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DOI：
10.1097/nen.0b013e31821cbd8b
发表时间：
2011-06-01
影响因子：
3.2
作者：
Dachs, Elisabet;Hereu, Marta;Esquerda, Josep E.
通讯作者：
Esquerda, Josep E.
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
9.8
作者：
Campbell, L;Potter, A;Davies, K
通讯作者：
Davies, K
影响因子：
3.5
作者：
Burlet, P;Huber, C;Lefebvre, S
通讯作者：
Lefebvre, S
DOI：
10.1083/jcb.119.3.493
发表时间：
1992-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Gavrieli Y;Sherman Y;Ben-Sasson SA
通讯作者：
Ben-Sasson SA