Suk Terry R, Part Caroline E, Zhang Jenny L, Nguyen Trina T, Heer Meghan M, Caballero-Gómez Alejandro, Grybas Veronica S, McKeever Paul M, Nguyen Benjamin, Ali Tahir, Callaghan Steve M, Woulfe John M, Robertson Janice, Rousseaux Maxime W C
University of Ottawa Brain and Mind Research Institute, Ottawa, ON, Canada.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.
Mol Neurodegener. 2025 Mar 28;20(1):38. doi: 10.1186/s13024-025-00826-z.
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors - such as cellular stressors - converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such exogenous stressors. We therefore set out to understand how SUMOylation may regulate TDP-43 in health and disease. We find that TDP-43 is regulated dynamically via SUMOylation in response to cellular stressors. When this process is blocked in vivo, we note age-dependent TDP-43 pathology and sex-specific behavioral deficits linking TDP-43 SUMOylation with aging and disease. We further find that SUMOylation is correlated with human aging and disease states. Collectively, this work presents TDP-43 SUMOylation as an early physiological response to cellular stress, disruption of which may confer a risk for TDP-43 proteinopathy.
肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）与TDP-43功能障碍密切相关。TDP-43的突变很少见，这表明外源性因素（如细胞应激源）的渐进性积累作用于TDP-43，在疾病发病机制中起关键作用。翻译后修饰（如SUMO化）在应对此类外源性应激源时发挥着重要作用。因此，我们着手了解SUMO化如何在健康和疾病状态下调节TDP-43。我们发现，TDP-43通过SUMO化对细胞应激源作出动态调节。当这一过程在体内被阻断时，我们注意到与年龄相关的TDP-43病理学变化以及将TDP-43 SUMO化与衰老和疾病联系起来的性别特异性行为缺陷。我们进一步发现，SUMO化与人类衰老和疾病状态相关。总的来说，这项研究表明TDP-43 SUMO化是对细胞应激的一种早期生理反应，其破坏可能会导致TDP-43蛋白病风险增加。
