Huntingtin Aggregation in Huntington’s Disease: From Protein Misfolding to Disease Mechanisms

Huntington’s disease (HD) is caused by a CAG repeat expansion in exon 1 of the HTT gene, producing a huntingtin protein with an elongated polyglutamine tract that misfolds, fragments, and aggregates. Among the many facets of huntingtin biology, aggregation sits at the heart of HD pathogenesis, yet its significance has been somewhat overlooked in recent years. How huntingtin misfolds, how oligomers and fibrils form and spread, and how these species relate to neuronal dysfunction remain central and incompletely answered questions.Recent advances have made these questions newly tractable. Cryo-electron microscopy is revealing the architecture of full-length huntingtin and its fibrillar assemblies. Genetic studies have identified DNA mismatch repair genes as modifiers of disease onset, placing somatic CAG repeat expansion, and the aggregation-prone species it generates, closer to the centre of pathogenesis. Meanwhile, the clinical setbacks of non-selective huntingtin-lowering strategies have underscored the need to understand both wild-type huntingtin function and the molecular events that drive aggregate formation.This Research Topic aims to bring together current and emerging research on huntingtin aggregation and the molecular events linking polyglutamine expansion to disease. By centring on aggregation, it seeks to connect structural, cell biological, genetic, and translational perspectives, and to clarify the points at which therapeutic intervention may be most effective. We welcome original research, reviews, mini reviews, methods papers, and perspectives.Areas of interest include, but are not limited to:Aggregation and amyloid formation: oligomer and fibril structure, liquid-liquid phase separation, seeding, intercellular propagation, and the relationship between inclusion formation and toxicity.Protein structure and conformation: full-length huntingtin architecture, HEAT repeat domains, polyglutamine tract conformation, huntingtin-HAP40 complexes, and cryo-EM or computational structural approaches relevant to misfolding and assembly.Post-translational modifications and proteolytic processing: phosphorylation, ubiquitination, SUMOylation, acetylation, palmitoylation, and cleavage by calpains, caspases, and other proteases; effects on stability, localisation, fragment generation, and aggregation propensity.Huntingtin interactome: protein-protein interactions in health and disease, effects of polyglutamine expansion on interaction networks, and modulation of huntingtin processing and aggregation by interactors.Somatic CAG repeat instability: mechanisms of expansion in neuronal and non-neuronal tissues, roles of mismatch repair proteins (MSH3, PMS1, FAN1), and implications for the generation of aggregation-prone species, onset, progression, and therapy.Normal huntingtin function: vesicular transport, BDNF trafficking, transcriptional regulation, autophagy, ciliogenesis, embryonic development, and implications for huntingtin-lowering therapies and aggregate clearance.Huntingtin-directed therapeutic strategies: antisense oligonucleotides, RNA interference, zinc finger repressors, allele-selective approaches, splicing modulators, targeted protein degradation, and approaches aimed at preventing or reversing aggregation, with lessons from clinical trials.Model systems and technologies: knock-in and transgenic animals, iPSC-derived neurons and organoids, aggregation assays, and multi-omics or imaging approaches applied to huntingtin misfolding and aggregation.By centring on huntingtin aggregation, this Research Topic seeks to bridge structural, cell biological, genetic, and translational perspectives and to clarify the molecular events at which therapeutic intervention may be most effective. Topic editors: Jonasz Jeremiasz Weber, Emily Sontag Source: https://www.frontiersin.org/research-topics/82802/huntingtin-aggregation-in-huntingtons-disease-from-protein-misfolding-to-disease-mechanisms