Novel pathological pathway of ALS/FTLD-U

泛素（UBQLN） 2定位于由als连锁分子OPTN （OPTN）形成的内体囊泡中，并在氨基酸饥饿后与自噬过程的启动物ULK1共定位。optn -囊泡泛素和p62免疫阳性。OPTN中与als相关的突变（E478G）破坏了囊泡的形成。与als相关的UBQLN2突变增加了UBQLN2的聚集和包涵体的形成，导致optn -囊泡错位。UBQLN2被发现是OPTN和ftd相关分泌因子前颗粒蛋白水平的有效调节剂，可能通过内体系统，而als相关突变扰乱了这些功能后果。本研究表明，与als相关的OPTN和UBQLN2突变干扰了特定内体囊泡的构成，表明这些囊泡参与蛋白质稳态，这些蛋白质在常见的病理过程中起作用。

Ubiquilin (UBQLN) 2 localized in endosomal vesicles formed by the ALS-linked molecule optineurin (OPTN) and also co-localized with an initiator of the autophagic process, ULK1, after amino acid starvation. OPTN-vesicles were ubiquitin- and p62-immunopositive. An ALS-linked mutation (E478G) in OPTN abolished vesicle formation. ALS-linked mutations in UBQLN2 additively enhanced UBQLN2 aggregation and formation of inclusion bodies, resulting in mislocation from OPTN-vesicles. UBQLN2 was found to be a potent regulator of the levels of OPTN and the FTD-linked secretory factor progranulin, possibly via the endosomal system, and ALS-linked mutations disturbed these functional consequences. This study demonstrates that ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes.