ArticleThe Journal of biological chemistry2012
Identification of novel potentially toxic oligomers formed in vitro from mammalian-derived expanded huntingtin exon-1 protein.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 64 papers.
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Who cites it
64 citing papers in PubMed, 129 citations in OpenAlex.
- Transient Interdomain Interactions Modulate the Monomeric Structural Ensemble and Self-Assembly of Huntingtin Exon 1.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Direct Observation of Secondary Nucleation in Huntingtin Amyloid Formation by High-Speed Atomic Force Microscopy.Journal of the American Chemical Society · 2025Article
- Loss of FIC-1-mediated AMPylation activates the UPRER and upregulates cytosolic HSP70 chaperones to suppress polyglutamine toxicity.PLoS genetics · 2025Article
- Molecular mechanisms of amyloid inhibition: an NMR-driven framework with polyphenols as a case study.Frontiers in molecular biosciences · 2025Article
- Why Is Arginine the Only Amino Acid That Inhibits Polyglutamine Monomers from Taking on Toxic Conformations?ACS chemical neuroscience · 2024Article
- Protein modification in neurodegenerative diseases.MedComm · 2024Review
- Reviewing the Structure-Function Paradigm in Polyglutamine Disorders: A Synergistic Perspective on Theoretical and Experimental Approaches.International journal of molecular sciences · 2024Review
- Neuropathogenesis-on-chips for neurodegenerative diseases.Nature communications · 2024Review
- Article
- The HSPB1-p62/SQSTM1 functional complex regulates the unconventional secretion and transcellular spreading of the HD-associated mutant huntingtin protein.Human molecular genetics · 2023Article
- The structure of pathogenic huntingtin exon 1 defines the bases of its aggregation propensity.Nature structural & molecular biology · 2023Article
- Cell Rearrangement and Oxidant/Antioxidant Imbalance in Huntington's Disease.Antioxidants (Basel, Switzerland) · 2023Review
- Spermatozoan Metabolism as a Non-Traditional Model for the Study of Huntington's Disease.International journal of molecular sciences · 2022Review
- Passive immunization against phosphorylated tau improves features of Huntington's disease pathology.Molecular therapy : the journal of the American Society of Gene Therapy · 2022Article
- Emerging Therapies for Huntington's Disease - Focus on N-Terminal Huntingtin and Huntingtin Exon 1.Biologics : targets & therapy · 2022Review
- Amplification of neurotoxic HTTex1 assemblies in human neurons.Neurobiology of disease · 2021Article
- Macromolecular crowding in solution alters huntingtin interaction and aggregation at interfaces.Colloids and surfaces. B, Biointerfaces · 2021Article
- Membrane Interactions Accelerate the Self-Aggregation of Huntingtin Exon 1 Fragments in a Polyglutamine Length-Dependent Manner.International journal of molecular sciences · 2021Article
- When Good Kinases Go Rogue: GSK3, p38 MAPK and CDKs as Therapeutic Targets for Alzheimer's and Huntington's Disease.International journal of molecular sciences · 2021Review
- Protein Aggregation Inhibitors as Disease-Modifying Therapies for Polyglutamine Diseases.Frontiers in neuroscience · 2021Review
4 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
14 authors at 5 institutions in 1 country.
Funding
Abstract
Huntington disease is a genetic neurodegenerative disorder that arises from an expanded polyglutamine region in the N terminus of the HD gene product, huntingtin. Protein inclusions comprised of N-terminal fragments of mutant huntingtin are a characteristic feature of disease, though are likely to play a protective role rather than a causative one in neurodegeneration. Soluble oligomeric assemblies of huntingtin formed early in the aggregation process are candidate toxic species in HD. In the present study, we established an in vitro system to generate recombinant huntingtin in mammalian cells. Using both denaturing and native gel analysis, we have identified novel oligomeric forms of mammalian-derived expanded huntingtin exon-1 N-terminal fragment. These species are transient and were not previously detected using bacterially expressed exon-1 protein. Importantly, these species are recognized by 3B5H10, an antibody that recognizes a two-stranded hairpin conformation of expanded polyglutamine believed to be associated with a toxic form of huntingtin. Interestingly, comparable oligomeric species were not observed for expanded huntingtin shortstop, a 117-amino acid fragment of huntingtin shown previously in mammalian cell lines and transgenic mice, and here in primary cortical neurons, to be non-toxic. Further, we demonstrate that expanded huntingtin shortstop has a reduced ability to form amyloid-like fibrils characteristic of the aggregation pathway for toxic expanded polyglutamine proteins. Taken together, these data provide a possible candidate toxic species in HD. In addition, these studies demonstrate the fundamental differences in early aggregation events between mutant huntingtin exon-1 and shortstop proteins that may underlie the differences in toxicity.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.