Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, Virginia, USA.
Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan, USA.
JCI Insight. 2024 Nov 8;9(21):e174725. doi: 10.1172/jci.insight.174725.
Recent studies have identified multiple genetic variants of SEL1L-HRD1 endoplasmic reticulum-associated degradation (ERAD) in humans with neurodevelopmental disorders and locomotor dysfunctions, including ataxia. However, the relevance and importance of SEL1L-HRD1 ERAD in the pathogenesis of ataxia remain unexplored. Here, we showed that SEL1L deficiency in Purkinje cells leads to early-onset progressive cerebellar ataxia with progressive loss of Purkinje cells with age. Mice with Purkinje cell-specific deletion of SEL1L (Sel1LPcp2Cre) exhibited motor dysfunction beginning around 9 weeks of age. Transmission electron microscopy analysis revealed dilated ER and fragmented nuclei in Purkinje cells of adult Sel1LPcp2Cre mice, indicative of altered ER homeostasis and cell death. Finally, loss of Purkinje cells was associated with a secondary neurodegeneration of granular cells, as well as robust activation of astrocytes and proliferation of microglia, in the cerebellums of Sel1LPcp2Cre mice. These data demonstrate the pathophysiological importance of SEL1L-HRD1 ERAD in Purkinje cells in the pathogenesis of cerebellar ataxia.
最近的研究已经在具有神经发育障碍和运动功能障碍的人类中发现了多个 SEL1L-HRD1 内质网相关降解（ERAD）的遗传变异体，包括共济失调。然而，SEL1L-HRD1 ERAD 在共济失调发病机制中的相关性和重要性仍未被探索。在这里，我们表明，浦肯野细胞中的 SEL1L 缺乏会导致早发性进行性小脑共济失调，随着年龄的增长，浦肯野细胞逐渐丧失。浦肯野细胞特异性缺失 SEL1L 的小鼠（Sel1LPcp2Cre）在大约 9 周龄时开始出现运动功能障碍。透射电子显微镜分析显示，成年 Sel1LPcp2Cre 小鼠的浦肯野细胞中内质网扩张和核碎裂，表明内质网稳态和细胞死亡发生改变。最后，浦肯野细胞的丧失与颗粒细胞的继发性神经退行性变、星形胶质细胞的强烈激活和小胶质细胞的增殖有关，在 Sel1LPcp2Cre 小鼠的小脑。这些数据表明 SEL1L-HRD1 ERAD 在浦肯野细胞中在小脑共济失调的发病机制中具有病理生理学意义。
