Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy
Intermediate filament aggregates cause mitochondrial dysmotility and increase energy demands in giant axonal neuropathy
复制标题
DOI：
10.1093/hmg/ddw081
复制
发表时间：
2016-06-01
影响因子：
3.5
通讯作者：
Opal, Puneet
中科院分区：
文献类型：
--
作者：
Israeli, Eitan;Dryanovski, Dilyan I.;Opal, Puneet
中间丝（IF）是从细胞核延伸到细胞膜的细胞骨架聚合物，赋予细胞形状和形式。IFs的异常积累参与了许多神经退行性疾病的发病机制，但没有一种像巨大轴突神经病（GAN）那样清楚，GAN是由编码gigaxonin的GAN突变引起的破坏性疾病。患者表现出早期和严重的周围神经系统退化沿着IF积累，但很难将GAN突变与任何特定的功能障碍联系起来，部分原因是GAN缺失小鼠具有非常轻微的表型。因此，我们建立了一个强大的背根神经节神经元模型，反映了GAN的关键细胞事件。我们证明，gigaxonin是至关重要的泛素-蛋白酶体降解的神经元IF。此外，IF积累损害线粒体运动，并与代谢和氧化应激有关。这些结果对其他神经系统疾病的病理包括IF积累的影响。
Intermediate filaments (IFs) are cytoskeletal polymers that extend from the nucleus to the cell membrane, giving cells their shape and form. Abnormal accumulation of IFs is involved in the pathogenesis of number neurodegenerative diseases, but none as clearly as giant axonal neuropathy (GAN), a ravaging disease caused by mutations in GAN, encoding gigaxonin. Patients display early and severe degeneration of the peripheral nervous system along with IF accumulation, but it has been difficult to link GAN mutations to any particular dysfunction, in part because GAN null mice have a very mild phenotype. We therefore established a robust dorsal root ganglion neuronal model that mirrors key cellular events underlying GAN. We demonstrate that gigaxonin is crucial for ubiquitin-proteasomal degradation of neuronal IF. Moreover, IF accumulation impairs mitochondrial motility and is associated with metabolic and oxidative stress. These results have implications for other neurological disorders whose pathology includes IF accumulation.