Department of Neurology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, 3-1 Aoyama-machi, Kure 737-0023, Japan.
Department of Epidemiology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8553, Japan.
Neurobiol Dis. 2021 Jan;148:105215. doi: 10.1016/j.nbd.2020.105215. Epub 2020 Dec 6.
We previously showed that optineurin (OPTN) mutations lead to the development of amyotrophic lateral sclerosis. The association between OPTN mutations and the pathogenesis of amyotrophic lateral sclerosis remains unclear. To investigate the mechanism underlying its pathogenesis, we generated Optn knockout mice. We evaluated histopathological observations of these mice and compared with those of OPTN- amyotrophic lateral sclerosis cases to investigate the mechanism underlying the pathogenesis of amyotrophic lateral sclerosis caused by OPTN mutations. The Optn (-/-) mice presented neuronal autophagic vacuoles immunopositive for charged multivesicular body protein 2b, one of the hallmarks of granulovacuolar degenerations, in the cytoplasm of spinal cord motor neurons at the age of 8 months and the OPTN- amyotrophic lateral sclerosis case with homozygous Q398X mutation. In addition, Optn (-/-) mice showed TAR-DNA binding protein 43/sequestosome1/p62 -positive cytoplasmic inclusions and the clearance of nuclear TAR-DNA binding protein 43. The axonal degeneration of the sciatic nerves was observed in Optn (-/-) mice. However, we could not observe significant differences in survival time, body weight, and motor functions, at 24 months. Our findings suggest that homozygous OPTN deletion or mutations might result in autophagic dysfunction and TAR-DNA binding protein 43 mislocalization, thereby leading to neurodegeneration of motor neurons. These findings indicate that the Optn (-/-) mice recapitulate both common and specific pathogenesis of amyotrophic lateral sclerosis associated with autophagic abnormalities. Optn (-/-) mice could serve as a mouse model for the development of therapeutic strategies.
我们之前已经表明，视神经病变（OPTN）突变会导致肌萎缩性侧索硬化症的发生。但是 OPTN 突变与肌萎缩性侧索硬化症发病机制之间的联系尚不清楚。为了研究其发病机制，我们构建了 Optn 敲除小鼠。我们评估了这些小鼠的组织病理学观察结果，并与 OPTN-肌萎缩性侧索硬化症病例进行比较，以研究 OPTN 突变引起的肌萎缩性侧索硬化症发病机制。在 8 月龄时，Optn（-/-）小鼠的脊髓运动神经元细胞质中出现了神经元自噬空泡，这些空泡免疫阳性反应为带电荷的多泡体蛋白 2b，这是颗粒状空泡变性的标志之一，与 OPTN-肌萎缩性侧索硬化症病例中的纯合 Q398X 突变相同。此外，Optn（-/-）小鼠还出现了 TAR-DNA 结合蛋白 43/自噬相关蛋白 1/p62 阳性的细胞质包涵体以及核 TAR-DNA 结合蛋白 43 的清除。Optn（-/-）小鼠的坐骨神经也出现了轴突变性。然而，在 24 个月时，我们没有观察到生存时间、体重和运动功能的显著差异。我们的研究结果表明，OPTN 缺失或突变可能导致自噬功能障碍和 TAR-DNA 结合蛋白 43 定位错误，从而导致运动神经元的神经退行性变。这些发现表明，Optn（-/-）小鼠重现了与自噬异常相关的肌萎缩性侧索硬化症的共同和特定发病机制。Optn（-/-）小鼠可能成为开发治疗策略的小鼠模型。
