约翰霍普金斯大学Jiou Wang课题组宣布他们的最新研究提出了UBQLN2将蛋白质毒性与神经变性中的脂质代谢联系起来。该研究于2026年3月30日发表于国际一流学术期刊《自然—神经科学》杂志上。

通过对含有UBQLN2突变的诱导多能干细胞（iPSC）衍生神经元的多组学分析，该课题组发现UBQLN2是连接脂质失调和蛋白质平衡的分子枢纽，其扰动导致神经退行性变。UBQLN2介导了ILVBL（乙酰乳酸合成酶样蛋白）和ALDH3A2（醛脱氢酶3家族成员A2）的降解，这两种酶是与脂滴和神经元活力相关的线粒体脂质分解代谢所必需的。ALS/ FTD相关的UBQLN2突变和TAR DNA结合蛋白43（TDP-43）病理损害ILVBL和ALDH3A2的降解，导致代谢功能障碍和神经变性。恢复UBQLN2 - ILVBL/ALDH3A2轴可减弱神经元、类器官和小鼠的神经退行性表型，确立UBQLN2作为ALS/FTD及其他相关神经退行性疾病代谢稳态的关键调节因子。

据了解，蛋白质稳态和脂质代谢是神经退行性疾病中经常中断的重要过程。然而，它们在肌萎缩侧索硬化症（ALS）和额颞叶痴呆（FTD）等疾病中的交叉机制尚不清楚。泛素2 （UBQLN2）是与ALS/FTD相关的蛋白质量控制因子。

附：英文原文

Title: UBQLN2 links proteotoxicity with lipid metabolism in neurodegeneration

Author: Liu, Yang, Huang, Zhiyuan, Hsu, Yu-Wen, Deme, Pragney, Frankenfield, Ashley M., Wu, Suheng, Zhao, Xiaofeng, Liu, Honghe, Zhang, Tao, Alexander, Elizabeth J., Liu, Mingming, Zhang, Yanjun, Wang, Haocheng, Zhou, Yixin, Monteiro, Mervyn J., Hao, Ling, Haughey, Norman J., Wang, Jiou

Issue&Volume: 2026-03-30

Abstract: Protein homeostasis and lipid metabolism are essential processes frequently disrupted in neurodegenerative diseases. However, their mechanistic intersection in disorders such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. Ubiquilin 2 (UBQLN2) is a protein quality control factor linked to ALS/FTD. Through multi-omic analyses of induced pluripotent stem cell (iPSC)-derived neurons harboring disease-associated UBQLN2 mutations, we uncovered UBQLN2 as a molecular hub linking lipid dysregulation and proteostasis, the perturbation of which contributes to neurodegeneration. UBQLN2 mediated the degradation of ILVBL (acetolactate synthase-like protein) and ALDH3A2 (aldehyde dehydrogenase 3 family member A2), two enzymes essential for mitochondrial lipid catabolism associated with lipid droplets and neuronal viability. ALS/FTD-linked UBQLN2 mutations and TAR DNA-binding protein 43 (TDP-43) pathology impair the degradation of ILVBL and ALDH3A2, leading to metabolic dysfunction and neurodegeneration. Restoring the UBQLN2–ILVBL/ALDH3A2 axis attenuates neurodegenerative phenotypes in neurons, organoids and mice, establishing UBQLN2 as a critical regulator of metabolic homeostasis in ALS/FTD and other related neurodegenerative diseases.

DOI: 10.1038/s41593-026-02226-y

Source: https://www.nature.com/articles/s41593-026-02226-y