TY - JOUR TI - A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis AU - Edens, Brittany M AU - Yan, Jianhua AU - Miller, Nimrod AU - Deng, Han-Xiang AU - Siddique, Teepu AU - Ma, Yongchao C A2 - West, Anne E VL - 6 PY - 2017 DA - 2017/05/02 SP - e25453 C1 - eLife 2017;6:e25453 DO - 10.7554/eLife.25453 UR - https://doi.org/10.7554/eLife.25453 AB - The etiological underpinnings of amyotrophic lateral sclerosis (ALS) are complex and incompletely understood, although contributions to pathogenesis by regulators of proteolytic pathways have become increasingly apparent. Here, we present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. We further demonstrate that the ALS-associated UBQLN4 variant impairs proteasomal function, and identify the Wnt signaling pathway effector beta-catenin as a UBQLN4 substrate. Inhibition of beta-catenin function rescues the UBQLN4 variant-induced motor axon phenotypes. These findings provide a strong link between the regulation of axonal morphogenesis and a new ALS-associated gene variant mediated by protein degradation pathways. KW - UBQLN4 KW - beta-catenin KW - ubiquitin proteasome system (UPS) KW - ALS KW - axon morphogenesis KW - neurodegeneration JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -