Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates

• Published in: Communications biology Vol. 4; no. 1; p. 849
• Main Authors: Galaz-Montoya, Jesús G., Shahmoradian, Sarah H., Shen, Koning, Frydman, Judith, Chiu, Wah
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.07.2021; Nature Publishing Group; Springer Nature; Nature Portfolio
• Subjects: 101/28; 14/63; 631/337/470/2284; 631/535/1258/1260; 82/29; 82/80; 82/83; BASIC BIOLOGICAL SCIENCES; Biology; Biomedical and Life Sciences; Cell fusion; cryoelectron tomography; Dehydration; Filaments; Fixatives; Glutamine; Huntingtin; Huntington's disease; Huntingtons disease; Life Sciences; Mutants; Neurotoxicity; Polyglutamine diseases; protein aggregation; Tomography; Trinucleotide repeat diseases
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-021-02360-2

Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. The formation and topology of filamentous mHTT inclusions in the brain (hallmarks of HD implicated in neurotoxicity) remain elusive. Using cryo-electron tomography and subtomogram averaging, here we show that mHTT exon 1 and polyQ-only aggregates in vitro are structurally heterogenous and filamentous, similar to prior observations with other methods. Yet, we find filaments in both types of aggregates under ~2 nm in width, thinner than previously reported, and regions forming large sheets. In addition, our data show a prevalent subpopulation of filaments exhibiting a lumpy slab morphology in both aggregates, supportive of the polyQ core model. This provides a basis for future cryoET studies of various aggregated mHTT and polyQ constructs to improve their structure-based modeling as well as their identification in cells without fusion tags. Galaz-Montoya et al. report nanometer-resolution 3D cryo-electron tomography structures of mutant huntingtin (mHTT) and polyglutamine-only (polyQ) filaments in large aggregates free of stains, fixatives, tags, or dehydration artifacts. These results provide a framework for future structural studies of mHTT and polyQ aggregates, thereby improving our understanding of polyQ disorders such as Huntington disease.