Novel pathological pathway of ALS/FTLD-U

泛素（UBQLN）2定位于由ALS连接的分子视神经磷酸酶（OPTN）形成的内体囊泡中，并且在氨基酸饥饿后与自噬过程的起始物ULK 1共定位。OPTN囊泡是泛素和p62免疫阳性。OPTN中的ALS连锁突变（E478G）消除了囊泡形成。UBQLN 2中的ALS连锁突变增加了UBQLN 2的聚集和包涵体的形成，导致从OPTN囊泡的错误定位。发现UBQLN 2是OPTN和FTD相关分泌因子颗粒蛋白前体水平的有效调节剂，可能通过内体系统，ALS相关突变扰乱了这些功能结果。这项研究表明，ALS连锁突变的OPTN和UBQLN 2干扰特定的内体囊泡的构成，这表明囊泡参与蛋白质稳态，这些蛋白质在共同的病理过程中发挥作用。

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.