Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice.
Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice.
复制标题
增强存活运动神经元表达可延长突变 TDP-43 小鼠的寿命并减轻神经退行性变。
DOI：
10.1093/hmg/ddw247
复制
发表时间：
2016
影响因子：
3.5
通讯作者：
B. J. Turner
中科院分区：
文献类型：
--
作者：
Nirma D Perera;Rebecca K. Sheean;P. Crouch;Anthony R. White;M. Horne;B. J. Turner
在脊髓性肌萎缩症(SMA)和肌萎缩侧索硬化症(ALS)中，RNA结合蛋白存活运动神经元(SMN)和TAR DNA结合蛋白43(TDP-43)的缺陷分别导致运动神经元进行性变性。虽然运动神经元中SMN蛋白的低水平会导致SMA，但最近的研究表明，SMN的水平和功能异常与ALS的发病有关。在这里，我们确定SMN蛋白在雄性转基因突变TDP-43A315T小鼠的脊髓和皮质运动神经元中早期和进行性上调。在TDP-43A315T小鼠运动神经元中发现含有TDP-43和HUR的胞质SMN聚集体，这与SMN掺入应激颗粒一致。为了测试增加SMN水平在TDP-43蛋白病变中的影响，我们证明了TDP-43A315T小鼠中人SMN的神经元过表达推迟了症状的出现和延长了生存时间。SMN上调还能对抗TDP-43A315T小鼠脊髓运动神经元的变性，减轻星形胶质细胞和小胶质细胞的激活，恢复AMP激酶的激活。我们还发现，另一种导致运动神经元脆弱性的因子雄激素受体(AR)在雄性TDP-43A315T小鼠的脊髓中的表达减少。这些结果表明，在突变型TDP-43介导的ALS模型中，运动神经元中SMN的过度表达通过改善病理征象来减缓疾病的发生和转归。因此，在ALS中使用药物或基因治疗药物来增加SMN水平的进一步方法可能是必要的。我们的数据还加强了ALS和脊髓延髓性肌萎缩症(SBMA)之间的新的潜在联系，SBMA是另一种由运动神经元AR功能降低介导的运动神经退行性疾病。
Defects in the RNA-binding proteins survival motor neuron (SMN) and TAR DNA-binding protein 43 (TDP-43) cause progressive motor neuron degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. While low levels of SMN protein in motor neurons result in SMA, recent studies implicate abnormal SMN levels and function in ALS pathogenesis. Here, we determine that SMN protein is upregulated early and progressively in spinal and cortical motor neurons of male transgenic mutant TDP-43A315T mice. Cytoplasmic SMN aggregates that contain TDP-43 and HuR were identified in motor neurons of TDP-43A315T mice, consistent with the incorporation of SMN into stress granules. To test the impact of augmenting SMN levels in TDP-43 proteinopathy, we demonstrate that neuronal overexpression of human SMN in TDP-43A315T mice delayed symptom onset and prolonged survival. SMN upregulation also countered motor neuron degeneration, attenuated activation of astrocytes and microglia and restored AMP kinase activation in spinal cords of TDP-43A315T mice. We also reveal that expression of another factor conferring motor neuron vulnerability, androgen receptor (AR), is reduced in spinal cords of male TDP-43A315T mice. These results establish that SMN overexpression in motor neurons slows disease onset and outcome by ameliorating pathological signs in this model of mutant TDP-43-mediated ALS. Further approaches to augment SMN levels using pharmacological or gene therapy agents may therefore be warranted in ALS. Our data also reinforce a novel potential link between ALS and spinal bulbar muscular atrophy (SBMA), another motor neurodegenerative disease mediated by reduced AR function in motor neurons.
影响因子：
34.7
作者：
Burghes, Arthur H. M.;Beattie, Christine E.
通讯作者：
Beattie, Christine E.
影响因子：
3.5
作者：
Gavrilina, Tatiana O.;McGovern, Vicki L.;Burghes, Arthur H. M.
通讯作者：
Burghes, Arthur H. M.
影响因子：
8.8
作者：
Yamazaki T;Chen S;Yu Y;Yan B;Haertlein TC;Carrasco MA;Tapia JC;Zhai B;Das R;Lalancette-Hebert M;Sharma A;Chandran S;Sullivan G;Nishimura AL;Shaw CE;Gygi SP;Shneider NA;Maniatis T;Reed R
通讯作者：
Reed R