Data_Sheet_1_Developmental Expression of Mutant PFN1 in Motor Neurons Impacts Neuronal Growth and Motor Performance of Young and Adult Mice.PDF

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 α-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.

肌萎缩侧索硬化症（Amyotrophic lateral sclerosis, ALS）是一种毁灭性神经退行性疾病，现有治疗手段有限且尚无治愈方案。2012年，研究者证实前纤维蛋白1（profilin 1）的突变可引发家族性肌萎缩侧索硬化症（familial ALS, fALS）。本研究探究了发育阶段小鼠脊髓内突变型前纤维蛋白1表达的功能影响。我们构建了一种新型转基因小鼠模型，该模型在Hb9启动子（Hb9 promoter）的调控下表达前纤维蛋白1 C71G突变体，可在发育阶段将靶标基因的表达限定于脊髓内的α运动神经元（α-motor neurons）中。转基因小鼠的胚胎表现出臂神经直径显著缩小以及孟德尔遗传模式偏离的表型。尽管成年小鼠体内未检测到转基因表达，但它们仍出现了显著的运动功能缺陷。转基因小鼠脊髓内的运动神经元数量显著减少。对老年转基因小鼠的运动神经元进行进一步分析后发现，其TDP-43与胆碱乙酰转移酶（choline acetyltransferase, ChAT）的表达水平均出现下降。尽管前纤维蛋白1 C71G仅在发育阶段表达，但成年小鼠仍出现了部分与ALS相关的病理特征与运动症状。本研究凸显了前纤维蛋白1在神经发育过程中的作用，以及该过程对后续ALS发病的潜在影响。