Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United States.
Department of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, United States.
Elife. 2023 Apr 11;12:e84382. doi: 10.7554/eLife.84382.
Mutations in the ubiquitin (Ub) chaperone ) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2) trigger heat stress-dependent neurodegeneration in . A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of or its coreceptor diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2 alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2 knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2 alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of and . The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.
泛素（Ub）伴侣蛋白突变导致 X 连锁形式的肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD），但其具体机制尚不清楚。本文中，作者研究发现，具有聚集倾向的 ALS 相关 UBQLN2（UBQLN2）突变体可触发 中的热应激依赖性神经退行性病变。遗传修饰筛选提示内溶酶体和轴突导向基因，包括轴突导向因子 UNC-5 的受体 netrin 受体，是 UBQLN2 毒性的关键调节因子。在表达 UBQLN2 等位基因的果蝇中，减少 或其核心受体 的基因剂量可减轻神经退行性表型，包括运动功能障碍、神经肌肉接头缺陷和寿命缩短。携带 UBQLN2 基因敲入突变的诱导多能干细胞（iPSCs）表现出溶酶体缺陷，而表达 UBQLN2 等位基因的诱导运动神经元（iMNs）则表现出细胞质 UBQLN2 包含物、神经突复杂性降低和生长锥缺陷，沉默 和 可部分逆转这些缺陷。综合研究结果表明，改变的生长锥动力学是 UBQLN2 相关 ALS/FTD 的保守发病机制。
