A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis
- Northwestern University Feinberg School of Medicine, United States
Abstract
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.
Article and author information
Author details
Yongchao Charles Ma
Funding
National Institute of Neurological Disorders and Stroke (NS094564)
- Yongchao Charles Ma
National Institute on Aging (AG043970)
- Yongchao Charles Ma
Hartwell Foundation
- Yongchao Charles Ma
Whitehall Foundation
- Yongchao Charles Ma
National Institute of Neurological Disorders and Stroke (NS078504)
- Teepu Siddique
Les Turner ALS Foundation
- Teepu Siddique
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal use in this study has been approved by the Institutional Animal Care and Use Committee (IACUC) of the Lurie Children's Hospital of Chicago (protocols 14-012 and 15-006). All studies were conducted in accordance with the US Public Health Service's Policy on Humane Care and Use of Laboratory Animals.
Human subjects: The use of human subjects in this study has been approved by the Northwestern University Institutional Review Board (IRB). Informed consent was obtained from all subjects.
Copyright
© 2017, Edens et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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A novel ALS-associated variant in UBQLN4 regulates motor axon morphogenesis
eLife 6:e25453.
https://doi.org/10.7554/eLife.25453
