ArticleHuman molecular genetics2018
Mutation-dependent aggregation and toxicity in a Drosophila model for UBQLN2-associated ALS.
Article in Human molecular genetics, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 39 citations in OpenAlex.
- ALS-associated exitron splicing produces UBQLN2 isoforms with distinct properties.bioRxiv : the preprint server for biology · 2026Article
- Neuronal guidance signaling in neurodegenerative diseases: Key regulators that function at neuron-glia and neuroimmune interfaces.Neural regeneration research · 2026Article
- UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.Biochemical Society transactions · 2025Review
- Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD.Frontiers in molecular neuroscience · 2025Article
- Chronic Oxidative Stress and Stress Granule Formation in UBQLN2 ALS Neurons: Insights into Neuronal Degeneration and Potential Therapeutic Targets.International journal of molecular sciences · 2024Article
- Article
- Disrupting the Balance of Protein Quality Control Protein UBQLN2 Accelerates Tau Proteinopathy.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2022Article
- Revealing the Mutational Spectrum in Southern Africans With Amyotrophic Lateral Sclerosis.Neurology. Genetics · 2022Article
- Amyotrophic lateral sclerosis (ALS) linked mutation in Ubiquilin 2 affects stress granule assembly via TIA-1.CNS neuroscience & therapeutics · 2022Article
- ALS-linked mutations impair UBQLN2 stress-induced biomolecular condensate assembly in cells.Journal of neurochemistry · 2021Article
- Fused in sarcoma regulates DNA replication timing and kinetics.The Journal of biological chemistry · 2021Article
- Shared and divergent phase separation and aggregation properties of brain-expressed ubiquilins.Scientific reports · 2021Article
- Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery.The Biochemical journal · 2020Review
- Honeybee products and edible insect powders improve locomotive and learning abilities of Ubiquilin-knockdown Drosophila.BMC complementary medicine and therapies · 2020Article
- Cell-Clearing Systems Bridging Repeat Expansion Proteotoxicity and Neuromuscular Junction Alterations in ALS and SBMA.International journal of molecular sciences · 2020Review
- Modeling Neurodegenerative Disorders inInternational journal of molecular sciences · 2020Review
- Promiscuous Roles of Autophagy and Proteasome in Neurodegenerative Proteinopathies.International journal of molecular sciences · 2020Review
- Key role of UBQLN2 in pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia.Acta neuropathologica communications · 2019Review
- ALS-Linked Mutations Affect UBQLN2 Oligomerization and Phase Separation in a Position- and Amino Acid-Dependent Manner.Structure (London, England : 1993) · 2019Article
- Non-Proteasomal UbL-UbA Family of Proteins in Neurodegeneration.International journal of molecular sciences · 2019Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
Members of the conserved ubiquilin (UBQLN) family of ubiquitin (Ub) chaperones harbor an antipodal UBL (Ub-like)-UBA (Ub-associated) domain arrangement and participate in proteasome and autophagosome-mediated protein degradation. Mutations in a proline-rich-repeat region (PRR) of UBQLN2 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD); however, neither the normal functions of the PRR nor impacts of ALS-associated mutations within it are well understood. In this study, we show that ALS mutations perturb UBQLN2 solubility and folding in a mutation-specific manner. Biochemical impacts of ALS mutations were additive, transferable to UBQLN1, and resulted in enhanced Ub association. A Drosophila melanogaster model for UBQLN2-associated ALS revealed that both wild-type and ALS-mutant UBQLN2 alleles disrupted Ub homeostasis; however, UBQLN2ALS mutants exhibited age-dependent aggregation and caused toxicity phenotypes beyond those seen for wild-type UBQLN2. Although UBQLN2 toxicity was not correlated with aggregation in the compound eye, aggregation-prone UBQLN2 mutants elicited climbing defects and neuromuscular junctions (NMJ) abnormalities when expressed in neurons. An UBA domain mutation that abolished Ub binding also diminished UBQLN2 toxicity, implicating Ub binding in the underlying pathomechanism. We propose that ALS-associated mutations in UBQLN2 disrupt folding and that both aggregated species and soluble oligomers instigate neuron autonomous toxicity through interference with Ub homeostasis.
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