Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
- University of Wisconsin-Madison, United States
- University of Pittsburgh Medical Center, United States
Abstract
Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.
Data availability
The RNA sequencing raw dataset has been deposited to Dryad and is accessible at https://doi.org/10.5061/dryad.tdz08kq39. All data generated or analyzed during this study are included in the manuscript.
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Transcriptomic analysis of UBQLN2-ALS DrosophilaDryad Digital Repository, doi:10.5061/dryad.tdz08kq39.
Article and author information
Author details
Funding
National Institute on Aging (R21 AG065896-01A1)
- Sang Hwa Kim
National Institutes of Health (1RF1AG069483-01A1)
- Randal S Tibbetts
National Cancer Institute (1R21 NS101661-01-A1)
- Randal S Tibbetts
ALS Association (Proteostatic regulation by Ubiquilins in ALS)
- Randal S Tibbetts
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2023, Kim 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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Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
eLife 12:e84382.
https://doi.org/10.7554/eLife.84382
