Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice
Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice
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DOI：
10.3389/fnmol.2019.00231
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发表时间：
2019-09-27
影响因子：
4.8
通讯作者：
Fath, Thomas
中科院分区：
文献类型：
--
作者：
Brettle, Merryn;Stefen, Holly;Fath, Thomas
肌萎缩侧索硬化症（ALS）是一种毁灭性的神经退行性疾病，治疗有限，无法治愈。2012年，基因型1突变被确定为家族性ALS （fALS）的一个原因。我们研究了突变型profil1在小鼠发育过程中对脊髓功能的影响。我们开发了一种新的小鼠模型，在Hb9启动子的控制下表达profilin 1 C71G，目标是在发育过程中表达脊髓的α -运动神经元。转基因小鼠的胚胎显示出臂神经直径显著减少和孟德尔遗传丧失的证据。尽管缺乏转基因表达，成年小鼠仍表现出明显的运动缺陷。转基因小鼠的脊髓运动神经元数量显著减少。对老龄转基因小鼠运动神经元的进一步分析显示，TDP-43和ChAT的表达水平降低。虽然profilin 1 C71G仅在发育过程中表达，但成年小鼠表现出一些与als相关的病理和运动症状。这项研究强调了profilin - 1在神经发育过程中的作用，以及它可能对晚期ALS产生的影响。
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment and no cure. Mutations in profilin 1 were identified as a cause of familial ALS (fALS) in 2012. We investigated the functional impact of mutant profilin 1 expression in spinal cords during mouse development. We developed a novel mouse model with the expression of profilin 1 C71G under the control of the Hb9 promoter, targeting expression to alpha-motor neurons in the spinal cord during development. Embryos of transgenic mice showed evidence of a significant reduction of brachial nerve diameter and a loss of Mendelian inheritance. Despite the lack of transgene expression, adult mice presented with significant motor deficits. Transgenic mice had a significant reduction in the number of motor neurons in the spinal cord. Further analysis of these motor neurons in aged transgenic mice revealed reduced levels of TDP-43 and ChAT expression. Although profilin 1 C71G was only expressed during development, adult mice presented with some ALS-associated pathology and motor symptoms. This study highlights the effect of profilin 1 during neurodevelopment and the impact that this may have in later ALS.