Safren Nathaniel, Dao Thuy P, Mohan Harihar Milaganur, Huang Camellia, Trotter Bryce, Castañeda Carlos A, Paulson Henry, Barmada Sami, Sharkey Lisa M
Department of Neurology, University of Michigan, Ann Arbor, MI, 48109-2200, USA.
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
Sci Rep. 2024 Mar 13;14(1):6049. doi: 10.1038/s41598-024-55582-9.
The ubiquitin-adaptor protein UBQLN2 promotes degradation of several aggregate-prone proteins implicated in neurodegenerative diseases. Missense UBQLN2 mutations also cause X-linked amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previously we demonstrated that the liquid-like properties of UBQLN2 molecular assemblies are altered by a specific pathogenic mutation, P506T, and that the propensity of UBQLN2 to aggregate correlated with neurotoxicity. Here, we systematically assess the effects of multiple, spatially distinct ALS/FTD-linked missense mutations on UBQLN2 aggregation propensity, neurotoxicity, phase separation, and autophagic flux. In contrast to what we observed for the P506T mutation, no other tested pathogenic mutant exhibited a clear correlation between aggregation propensity and neurotoxicity. These results emphasize the unique nature of pathogenic UBQLN2 mutations and argue against a generalizable link between aggregation propensity and neurodegeneration in UBQLN2-linked ALS/FTD.
泛素衔接蛋白UBQLN2可促进几种与神经退行性疾病相关的易聚集蛋白的降解。UBQLN2的错义突变也会导致X连锁肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）。此前我们证明，特定的致病突变P506T会改变UBQLN2分子聚集体的类液体特性，并且UBQLN2的聚集倾向与神经毒性相关。在此，我们系统地评估了多个空间上不同的与ALS/FTD相关的错义突变对UBQLN2聚集倾向、神经毒性、相分离和自噬通量的影响。与我们观察到的P506T突变不同，其他测试的致病突变在聚集倾向和神经毒性之间均未表现出明显的相关性。这些结果强调了致病UBQLN2突变的独特性质，并反对在与UBQLN2相关的ALS/FTD中聚集倾向与神经退行性变之间存在普遍联系的观点。
