ArticlePLoS genetics2012
Identification of human proteins that modify misfolding and proteotoxicity of pathogenic ataxin-1.
Article in PLoS genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 33 citations in OpenAlex.
- NeuroGeM, a knowledgebase of genetic modifiers in neurodegenerative diseases.BMC medical genomics · 2013Pooled it
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- Intranuclear inclusions of polyQ-expanded ATXN1 sequester RNA molecules.Frontiers in molecular neuroscience · 2023Article
- Analysis of Huntington's Disease Modifiers Using the Hyperbolic Mapping of the Protein Interaction Network.International journal of molecular sciences · 2022Article
- Review
- Between Interactions and Aggregates: The PolyQ Balance.Genome biology and evolution · 2021Article
- Oxidative Stress and Neurodegeneration: Interconnected Processes in PolyQ Diseases.Antioxidants (Basel, Switzerland) · 2021Review
- The Role of Low Complexity Regions in Protein Interaction Modes: An Illustration in Huntingtin.International journal of molecular sciences · 2021Article
- Chemical Biology Framework to Illuminate Proteostasis.Annual review of biochemistry · 2020Review
- Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery.Redox biology · 2020Article
- Comparative Analysis of Mutant Huntingtin Binding Partners in Yeast Species.Scientific reports · 2018Article
- Mediator tail subunits can form amyloid-like aggregates in vivo and affect stress response in yeast.Nucleic acids research · 2015Article
- Reduced SNAP-25 increases PSD-95 mobility and impairs spine morphogenesis.Cell death and differentiation · 2015Article
- Differential Occurrence of Interactions and Interaction Domains in Proteins Containing Homopolymeric Amino Acid Repeats.Frontiers in genetics · 2015Article
- Stem cell models of polyglutamine diseases and their use in cell-based therapies.Frontiers in neuroscience · 2015Article
- Identification of the mitochondrial MSRB2 as a binding partner of LG72.Cellular and molecular neurobiology · 2014Article
- Prion-like proteins sequester and suppress the toxicity of huntingtin exon 1.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- The palmitoyl acyltransferase HIP14 shares a high proportion of interactors with huntingtin: implications for a role in the pathogenesis of Huntington's disease.Human molecular genetics · 2014Article
- Association of polyalanine and polyglutamine coiled coils mediates expansion disease-related protein aggregation and dysfunction.Human molecular genetics · 2014Article
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Proteins with long, pathogenic polyglutamine (polyQ) sequences have an enhanced propensity to spontaneously misfold and self-assemble into insoluble protein aggregates. Here, we have identified 21 human proteins that influence polyQ-induced ataxin-1 misfolding and proteotoxicity in cell model systems. By analyzing the protein sequences of these modifiers, we discovered a recurrent presence of coiled-coil (CC) domains in ataxin-1 toxicity enhancers, while such domains were not present in suppressors. This suggests that CC domains contribute to the aggregation- and toxicity-promoting effects of modifiers in mammalian cells. We found that the ataxin-1-interacting protein MED15, computationally predicted to possess an N-terminal CC domain, enhances spontaneous ataxin-1 aggregation in cell-based assays, while no such effect was observed with the truncated protein MED15ΔCC, lacking such a domain. Studies with recombinant proteins confirmed these results and demonstrated that the N-terminal CC domain of MED15 (MED15CC) per se is sufficient to promote spontaneous ataxin-1 aggregation in vitro. Moreover, we observed that a hybrid Pum1 protein harboring the MED15CC domain promotes ataxin-1 aggregation in cell model systems. In strong contrast, wild-type Pum1 lacking a CC domain did not stimulate ataxin-1 polymerization. These results suggest that proteins with CC domains are potent enhancers of polyQ-mediated protein misfolding and aggregation in vitro and in vivo.
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