Sassone Jenny, Taiana Michela, Lombardi Raffaella, Porretta-Serapiglia Carla, Freschi Mattia, Bonanno Silvia, Marcuzzo Stefania, Caravello Francesca, Bendotti Caterina, Lauria Giuseppe
3rd Neurology Unit and
3rd Neurology Unit and.
Hum Mol Genet. 2016 Apr 15;25(8):1588-99. doi: 10.1093/hmg/ddw035. Epub 2016 Feb 9.
Growing evidence suggests that amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease that primarily affects motor neurons and, though less evidently, other neuronal systems. About 75% of sporadic and familial ALS patients show a subclinical degeneration of small-diameter fibers, as measured by loss of intraepidermal nerve fibers (IENFs), but the underlying biological causes are unknown. Small-diameter fibers are derived from small-diameter sensory neurons, located in dorsal root ganglia (DRG), whose biochemical hallmark is the expression of type III intermediate filament peripherin. We tested here the hypothesis that small-diameter DRG neurons of ALS mouse model SOD1(G93A)suffer from axonal stress and investigated the underlying molecular mechanism. We found that SOD1(G93A)mice display small fiber pathology, as measured by IENF loss, which precedes the onset of the disease. In vitro small-diameter DRG neurons of SOD1(G93A)mice show axonal stress features and accumulation of a peripherin splice variant, named peripherin56, which causes axonal stress through disassembling light and medium neurofilament subunits (NFL and NFM, respectively). Our findings first demonstrate that small-diameter DRG neurons of the ALS mouse model SOD1(G93A)display axonal stress in vitro and in vivo, thus sustaining the hypothesis that the effects of ALS disease spread beyond motor neurons. These results suggest a molecular mechanism for the small fiber pathology found in ALS patients. Finally, our data agree with previous findings, suggesting a key role of peripherin in the ALS pathogenesis, thus highlighting that DRG neurons mirror some dysfunctions found in motor neurons.
越来越多的证据表明，肌萎缩侧索硬化症（ALS）是一种多系统神经退行性疾病，主要影响运动神经元，虽然不太明显，但也会影响其他神经元系统。约75%的散发性和家族性ALS患者表现出小直径纤维的亚临床退化，这通过表皮内神经纤维（IENF）的丧失来衡量，但其潜在的生物学原因尚不清楚。小直径纤维源自位于背根神经节（DRG）的小直径感觉神经元，其生化标志是III型中间丝外周蛋白的表达。我们在此测试了ALS小鼠模型SOD1(G93A)的小直径DRG神经元遭受轴突应激的假说，并研究了其潜在的分子机制。我们发现，通过IENF丧失来衡量，SOD1(G93A)小鼠在疾病发作之前就表现出小纤维病理。体外培养的SOD1(G93A)小鼠的小直径DRG神经元表现出轴突应激特征以及一种名为外周蛋白56的外周蛋白剪接变体的积累，该变体通过拆解轻链和中链神经丝亚基（分别为NFL和NFM）导致轴突应激。我们的研究结果首次表明，ALS小鼠模型SOD1(G93A)的小直径DRG神经元在体外和体内均表现出轴突应激，从而支持了ALS疾病的影响超出运动神经元的假说。这些结果提示了ALS患者中发现的小纤维病理的分子机制。最后，我们的数据与先前的研究结果一致，表明外周蛋白在ALS发病机制中起关键作用，从而突出了DRG神经元反映了运动神经元中发现的一些功能障碍。
