Department of Neurobiology, The First Affiliated Hospital, Institute of Translational Medicine, School of Medicine, Zhejiang University, Zhejiang 310020, China.
Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China; Department of Rehabilitation Medicine, Huashan Hospital, Fudan University, Shanghai 200040, China.
Neuron. 2021 Jun 16;109(12):1949-1962.e6. doi: 10.1016/j.neuron.2021.04.023. Epub 2021 May 14.
Expansion of a hexanucleotide repeat GGGGCC (G4C2) in the intron of the C9ORF72 gene is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9-ALS/FTD). Transcripts carrying G4C2 repeat expansions generate neurotoxic dipeptide repeat (DPR) proteins, including poly-Gly-Ala (poly-GA), which tends to form protein aggregates. Here, we demonstrate that UBQLN2, another ALS/FTD risk factor, is recruited to reduce poly-GA aggregates and alleviate poly-GA-induced neurotoxicity. UBQLN2 could recognize HSP70 ubiquitination, which facilitates the UBQLN2-HSP70-GA complex formation and promotes poly-GA degradation. ALS/FTD-related UBQLN2 mutants fail to bind HSP70 and clear poly-GA aggregates. Disruption of the interaction between UBQLN2 and HSP70 inhibits poly-GA aggregation in C9-ALS/FTD iPSC-derived neurons. Finally, enhancing HSP70 by the chemical compound 17AAG at the adult stage mitigates behavioral defects in poly-GA animals. Our findings suggest a critical role of the UBQLN2-HSP70 axis in protein aggregate clearance in C9-ALS/FTD.
六核苷酸重复 GGGGCC（G4C2）在 C9ORF72 基因的内含子中扩张是肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）（C9-ALS/FTD）的最常见原因。携带 G4C2 重复扩展的转录本产生神经毒性二肽重复（DPR）蛋白，包括聚甘氨酸-丙氨酸（poly-GA），它往往形成蛋白质聚集体。在这里，我们证明另一个 ALS/FTD 风险因素 UBQLN2 被招募来减少 poly-GA 聚集体并减轻 poly-GA 诱导的神经毒性。UBQLN2 可以识别 HSP70 的泛素化，这有助于 UBQLN2-HSP70-GA 复合物的形成并促进 poly-GA 的降解。与 ALS/FTD 相关的 UBQLN2 突变体无法结合 HSP70 并清除 poly-GA 聚集体。破坏 UBQLN2 和 HSP70 之间的相互作用会抑制 C9-ALS/FTD iPSC 衍生神经元中的 poly-GA 聚集。最后，在成年期通过化学化合物 17AAG 增强 HSP70 可以减轻 poly-GA 动物的行为缺陷。我们的研究结果表明，UBQLN2-HSP70 轴在 C9-ALS/FTD 中的蛋白质聚集体清除中起着关键作用。
