Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2
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 ne...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2023-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/84382 |
| _version_ | 1797837571326214144 |
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| author | Sang Hwa Kim Kye D Nichols Eric N Anderson Yining Liu Nandini Ramesh Weiyan Jia Connor J Kuerbis Mark Scalf Lloyd M Smith Udai Bhan Pandey Randal S Tibbetts |
| author_facet | Sang Hwa Kim Kye D Nichols Eric N Anderson Yining Liu Nandini Ramesh Weiyan Jia Connor J Kuerbis Mark Scalf Lloyd M Smith Udai Bhan Pandey Randal S Tibbetts |
| author_sort | Sang Hwa Kim |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-09T15:27:01Z |
| format | Article |
| id | doaj.art-72192ff0353948d194af3bd44b77dd3a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-09T15:27:01Z |
| publishDate | 2023-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-72192ff0353948d194af3bd44b77dd3a2023-04-28T14:10:22ZengeLife Sciences Publications LtdeLife2050-084X2023-04-011210.7554/eLife.84382Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2Sang Hwa Kim0https://orcid.org/0000-0002-9245-4514Kye D Nichols1Eric N Anderson2Yining Liu3https://orcid.org/0000-0003-2632-7119Nandini Ramesh4Weiyan Jia5Connor J Kuerbis6Mark Scalf7Lloyd M Smith8https://orcid.org/0000-0002-6652-8639Udai Bhan Pandey9https://orcid.org/0000-0002-6267-0179Randal S Tibbetts10https://orcid.org/0000-0003-2245-2297Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesDepartment of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesDepartment of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesDepartment of Chemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Chemistry, University of Wisconsin-Madison, Madison, United StatesDepartment of Pediatrics, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, United StatesDepartment of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, United StatesMutations 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.https://elifesciences.org/articles/84382amyotrophic lateral sclerosisUBQLN2axon guidanceinduced motor neurongenetic screenprotein aggregation |
| spellingShingle | Sang Hwa Kim Kye D Nichols Eric N Anderson Yining Liu Nandini Ramesh Weiyan Jia Connor J Kuerbis Mark Scalf Lloyd M Smith Udai Bhan Pandey Randal S Tibbetts Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 eLife amyotrophic lateral sclerosis UBQLN2 axon guidance induced motor neuron genetic screen protein aggregation |
| title | Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 |
| title_full | Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 |
| title_fullStr | Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 |
| title_full_unstemmed | Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 |
| title_short | Axon guidance genes modulate neurotoxicity of ALS-associated UBQLN2 |
| title_sort | axon guidance genes modulate neurotoxicity of als associated ubqln2 |
| topic | amyotrophic lateral sclerosis UBQLN2 axon guidance induced motor neuron genetic screen protein aggregation |
| url | https://elifesciences.org/articles/84382 |
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