PDF(Pubmed)
Abstract：
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron degeneration in the central nervous system. Recent research has increasingly linked the activation of nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome to ALS pathogenesis. NLRP3 activation triggers Caspase 1 (CASP 1) auto-activation, leading to the cleavage of Gasdermin D (GSDMD) and pore formation on the cellular membrane. This process facilitates cytokine secretion and ultimately results in pyroptotic cell death, highlighting the complex interplay of inflammation and neurodegeneration in ALS. This study aimed to characterize the NLRP3 inflammasome components and their colocalization with cellular markers using the wobbler mouse as an ALS animal model. Firstly, we checked the levels of miR-223-3p because of its association with NLRP3 inflammasome activity. The wobbler mice showed an increased expression of miR-223-3p in the ventral horn, spinal cord, and cerebellum tissues. Next, increased levels of NLRP3, pro-CASP 1, cleaved CASP 1 (c-CASP 1), full-length GSDMD, and cleaved GDSMD revealed NLRP3 inflammasome activation in wobbler spinal cords, but not in the cerebellum. Furthermore, we investigated the colocalization of the aforementioned proteins with neurons, microglia, and astrocyte markers in the spinal cord tissue. Evidently, the wobbler mice displayed microgliosis, astrogliosis, and motor neuron degeneration in this tissue. Additionally, we showed the upregulation of protein levels and the colocalization of NLRP3, c-CASP1, and GSDMD in neurons, as well as in microglia and astrocytes. Overall, this study demonstrated the involvement of NLRP3 inflammasome activation and pyroptotic cell death in the spinal cord tissue of wobbler mice, which could further exacerbate the motor neuron degeneration and neuroinflammation in this ALS mouse model.
摘要：
肌萎缩侧索硬化(ALS)是一种以中枢神经系统运动神经元变性为特征的致命性神经退行性疾病。最近的研究越来越多地将核苷酸寡聚化结构域样受体蛋白3（NLRP3）炎性体的激活与ALS发病机理联系起来。NLRP3激活触发Caspase1（CASP1）自动激活，导致GasderminD（GSDMD）的裂解和细胞膜上的孔形成。该过程促进细胞因子分泌并最终导致焦转细胞死亡。突出了ALS中炎症和神经变性的复杂相互作用。这项研究旨在使用摇摆小鼠作为ALS动物模型来表征NLRP3炎性体成分及其与细胞标记物的共定位。首先,我们检查了miR-223-3p的水平,因为它与NLRP3炎性体活性相关.摇摆小鼠显示在腹角中miR-223-3p的表达增加，脊髓,和小脑组织.接下来,NLRP3，pro-CASP1，cleavedCASP1（c-CASP1），全长GSDMD，裂开的GDSMD显示摆动脊髓中的NLRP3炎性体激活，但不在小脑.此外，我们研究了上述蛋白质与神经元的共定位，小胶质细胞,和脊髓组织中的星形胶质细胞标记。显然,摇摆小鼠表现出小胶质细胞增生，星形胶质增生,和这个组织中的运动神经元变性。此外,我们显示了神经元中蛋白质水平的上调和NLRP3，c-CASP1和GSDMD的共定位，以及小胶质细胞和星形胶质细胞。总的来说,这项研究证明了NLRP3炎性体激活和焦化性细胞死亡参与了摇摆小鼠的脊髓组织，这可能进一步加剧该ALS小鼠模型的运动神经元变性和神经炎症。
