Kuźma-Kozakiewicz Magdalena, Chudy Agnieszka, Kaźmierczak Beata, Dziewulska Dorota, Usarek Ewa, Barańczyk-Kuźma Anna
Department of Neurology, Medical University of Warsaw, Warsaw, Poland.
Neurochem Res. 2013 Sep 28;38(12):2463-73. doi: 10.1007/s11064-013-1160-7.
Dynactin is a complex motor protein involved in the retrograde axonal transport disturbances of which may lead to amyotrophic lateral sclerosis (ALS). Mice with hSOD1G93A mutation develop ALS-like symptoms and are used as a model for the disease studies. Similar symptoms demonstrate Cra1 mice, with Dync1h1 mutation. Dynactin heavy (DCTN1) and light (DCTN3) subunits were studied in the CNS of humans with sporadic ALS (SALS), mice with hSOD1G93A (SOD1/+), Dync1h1 (Cra1/+), and double (Cra1/SOD1) mutation at presymptomatic and symptomatic stages. In SALS subjects, in contrast to control cases, expression of DCTN1-mRNA but not DCTN3-mRNA in the motor cortex was higher than in the sensory cortex. However, the mean levels of DCTN1-mRNA and protein were lower in both SALS cortexes and in the spinal cord than in control structures. DCTN3 was unchanged in brain cortexes but decreased in the spinal cord on both mRNA and protein levels. In all SALS tissues immunohistochemical analyses revealed degeneration and loss of neuronal cells, and poor expression of dynactin subunits. In SOD1/+ mice both subunits expression was significantly lower in the frontal cortex, spinal cord and hippocampus than in wild-type controls, especially at presymptomatic stage. Fewer changes occurred in Cra1/SOD1 and Cra1/+ mice.It can be concluded that in sporadic and SOD1-related ALS the impairment of axonal retrograde transport may be due to dynactin subunits deficiency and subsequent disturbances of the whole dynein/dynactin complex structure and function. The Dync1h1 mutation itself has slight negative effect on dynactin expression and it alleviates the changes caused by SOD1G93A mutation.
动力蛋白激活蛋白是一种复合运动蛋白，其参与的逆行轴突运输紊乱可能导致肌萎缩侧索硬化症（ALS）。携带hSOD1G93A突变的小鼠会出现类似ALS的症状，并被用作该疾病研究的模型。携带Dync1h1突变的Cra1小鼠也表现出类似症状。研究了散发性ALS（SALS）患者、携带hSOD1G93A（SOD1/+）、Dync1h1（Cra1/+）以及双突变（Cra1/SOD1）的小鼠在症状前期和症状期时中枢神经系统中动力蛋白激活蛋白重链（DCTN1）和轻链（DCTN3）亚基的情况。与对照病例相比，在SALS患者中，运动皮层中DCTN1 - mRNA的表达高于感觉皮层，但DCTN3 - mRNA的表达并非如此。然而，SALS患者的皮层和脊髓中DCTN1 - mRNA和蛋白的平均水平均低于对照结构。DCTN3在脑皮层中无变化，但在脊髓中的mRNA和蛋白水平均下降。在所有SALS组织中，免疫组织化学分析显示神经元细胞发生变性和丢失，动力蛋白激活蛋白亚基表达不佳。在SOD1/+小鼠中，两个亚基在额叶皮层、脊髓和海马体中的表达均显著低于野生型对照，尤其是在症状前期。Cra1/SOD1和Cra1/+小鼠中的变化较少。可以得出结论，在散发性和与SOD1相关的ALS中，轴突逆行运输受损可能是由于动力蛋白激活蛋白亚基缺乏以及随后整个动力蛋白/动力蛋白激活蛋白复合体结构和功能的紊乱所致。Dync1h1突变本身对动力蛋白激活蛋白的表达有轻微负面影响，但它减轻了由SOD1G93A突变引起的变化。
