Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism.
Neuron-specific knock-down of SMN1 causes neuron degeneration and death through an apoptotic mechanism.
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DOI：
10.1093/hmg/ddw119
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发表时间：
2016-06-15
影响因子：
3.5
通讯作者：
Di Schiavi E
中科院分区：
文献类型：
--
作者：
Gallotta I;Mazzarella N;Donato A;Esposito A;Chaplin JC;Castro S;Zampi G;Battaglia GS;Hilliard MA;Bazzicalupo P;Di Schiavi E
脊髓性肌萎缩症是一种破坏性疾病，其特征是脊髓前角运动神经元的特定亚类的变性和死亡。尽管20年前就发现了负责的基因，运动神经元存活基因1（SMN 1），但事实证明，很难在体内研究其作用。因此，关于这种分子的分子和细胞功能的一些关键问题仍然没有答案。我们开发了一个秀丽隐杆线虫模型的smn-1的功能丧失，使用神经元特异性RNA干扰策略，选择性地敲低smn-1在运动神经元的一个亚类。转基因动物呈现细胞自主的、年龄依赖性的运动神经元退化，检测为运动缺陷和靶神经元中突触前和细胞质荧光标记物的消失。这种变性导致神经元死亡，如对遗传和化学细胞死亡标记物的阳性反应所揭示的。我们发现，经典的细胞凋亡途径的基因参与smn-1介导的神经元死亡，这种表型可以通过人SMN 1的表达来拯救，这表明两个直系同源物之间的功能保守性。最后，我们确定Plastin 3/plst-1与smn-1在遗传上相互作用以防止变性，并且用丙戊酸治疗能够挽救变性表型。这些结果提供了新的见解的细胞和分子机制，导致运动神经元的损失时，SMN 1功能降低。
Spinal muscular atrophy is a devastating disease that is characterized by degeneration and death of a specific subclass of motor neurons in the anterior horn of the spinal cord. Although the gene responsible, survival motor neuron 1 (SMN1), was identified 20 years ago, it has proven difficult to investigate its effects in vivo. Consequently, a number of key questions regarding the molecular and cellular functions of this molecule have remained unanswered. We developed a Caenorhabditis elegans model of smn-1 loss-of-function using a neuron-specific RNA interference strategy to knock-down smn-1 selectively in a subclass of motor neurons. The transgenic animals presented a cell-autonomous, age-dependent degeneration of motor neurons detected as locomotory defects and the disappearance of presynaptic and cytoplasmic fluorescent markers in targeted neurons. This degeneration led to neuronal death as revealed by positive reactivity to genetic and chemical cell-death markers. We show that genes of the classical apoptosis pathway are involved in the smn-1-mediated neuronal death, and that this phenotype can be rescued by the expression of human SMN1, indicating a functional conservation between the two orthologs. Finally, we determined that Plastin3/plst-1 genetically interacts with smn-1 to prevent degeneration, and that treatment with valproic acid is able to rescue the degenerative phenotype. These results provide novel insights into the cellular and molecular mechanisms that lead to the loss of motor neurons when SMN1 function is reduced.
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影响因子：
64.5
作者：
LEFEBVRE, S;BURGLEN, L;MELKI, J
通讯作者：
MELKI, J
影响因子：
3.5
作者：
Ackermann, Bastian;Kroeber, Sandra;Wirth, Brunhilde
通讯作者：
Wirth, Brunhilde
影响因子：
--
作者：
Burt, Emma C.;Towers, Paula R.;Sattelle, David B.
通讯作者：
Sattelle, David B.
SMN是果蝇中感觉运动电路函数所必需的。
影响因子：
64.5
作者：
Imlach WL;Beck ES;Choi BJ;Lotti F;Pellizzoni L;McCabe BD
通讯作者：
McCabe BD
DOI：
10.1523/jneurosci.1536-12.2013
发表时间：
2013-04-10
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Dimitriadi M;Kye MJ;Kalloo G;Yersak JM;Sahin M;Hart AC
通讯作者：
Hart AC