ArticleHuman molecular genetics2018
Identification of distinct conformations associated with monomers and fibril assemblies of mutant huntingtin.
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, 49 citations in OpenAlex.
- Progressively reduced cerebral oxygen metabolism and elevated plasma NfL levels in the zQ175DN mouse model of Huntington's disease.Experimental neurology · 2025Article
- Pathobiology of the autophagy-lysosomal pathway in the Huntington's disease brain.Acta neuropathologica communications · 2025Article
- Protofibril Binding Peptides Recognize and Inhibit Huntingtin Amyloid FormationbioRxiv : the preprint server for biology · 2025Article
- Article
- Inhibitor-based modulation of huntingtin aggregation mechanisms mitigates fibril-induced cellular stress.Nature communications · 2025Article
- Article
- Pleiotropic effects of mutant huntingtin on retinopathy in two mouse models of Huntington's disease.Neurobiology of disease · 2025Article
- TDP43 and huntingtin Exon-1 undergo a conformationally specific interaction that strongly alters the fibril formation of both proteins.The Journal of biological chemistry · 2024Article
- Towards Standardizing Nomenclature in Huntington's Disease Research.Journal of Huntington's disease · 2024Review
- Fluorescent protein tagging promotes phase separation and alters the aggregation pathway of huntingtin exon-1.The Journal of biological chemistry · 2024Article
- Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.Neurobiology of disease · 2023Article
- Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model.bioRxiv : the preprint server for biology · 2023Article
- Benefits of global mutant huntingtin lowering diminish over time in a Huntington's disease mouse model.JCI insight · 2022Article
- Gut Bacteria Regulate the Pathogenesis of Huntington's Disease inFrontiers in neuroscience · 2022Article
- Hunting for the cause: Evidence for prion-like mechanisms in Huntington's disease.Frontiers in neuroscience · 2022Review
- Striatal Induction and Spread of the Huntington's Disease Protein: A Novel Rhes Route.Journal of Huntington's disease · 2022Review
- Amplification of neurotoxic HTTex1 assemblies in human neurons.Neurobiology of disease · 2021Article
- Shedding a new light on Huntington's disease: how blood can both propagate and ameliorate disease pathology.Molecular psychiatry · 2021Article
- Huntingtin fibrils with different toxicity, structure, and seeding potential can be interconverted.Nature communications · 2021Article
- Small, Seeding-Competent Huntingtin Fibrils Are Prominent Aggregate Species in Brains of zQ175 Huntington's Disease Knock-in Mice.Frontiers in neuroscience · 2021Article
Corrections and comments
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Authors and funding
15 authors at 3 institutions in 2 countries.
Funding
Abstract
The N-terminal fragments of mutant huntingtin (mHTT) misfold and assemble into oligomers, which ultimately bundle into insoluble fibrils. Conformations unique to various assemblies of mHTT remain unknown. Knowledge on the half-life of various multimeric structures of mHTT is also scarce. Using a panel of four new antibodies named PHP1-4, we have identified new conformations in monomers and assembled structures of mHTT. PHP1 and PHP2 bind to epitopes within the proline-rich domain (PRD), whereas PHP3 and PHP4 interact with motifs formed at the junction of polyglutamine (polyQ) and polyproline (polyP) repeats of HTT. The PHP1- and PHP2-reactive epitopes are exposed in fibrils of mHTT exon1 (mHTTx1) generated from recombinant proteins and mHTT assemblies, which progressively accumulate in the nuclei, cell bodies and neuropils in the brains of HD mouse models. Notably, electron microscopic examination of brain sections of HD mice revealed that PHP1- and PHP2-reactive mHTT assemblies are present in myelin sheath and in vesicle-like structures. Moreover, PHP1 and PHP2 antibodies block seeding and subsequent fibril assembly of mHTTx1 in vitro and in a cell culture model of HD. PHP3 and PHP4 bind to epitopes in full-length and N-terminal fragments of monomeric mHTT and binding diminishes as the mHTTx1 assembles into fibrils. Interestingly, PHP3 and PHP4 also prevent the aggregation of mHTTx1 in vitro highlighting a regulatory function for the polyQ-polyP motifs. These newly detected conformations may affect fibril assembly, stability and intercellular transport of mHTT.
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