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

Jesús G. Galaz-Montoya, Sarah H. Shahmoradian, Koning Shen, Judith Frydman, Wah Chiu
2021 Communications Biology  
AbstractHuntington 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
more » ... ervations 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.
doi:10.1038/s42003-021-02360-2 fatcat:fk3tfm2rrfeulip2z3ebuhmd3y