Abstract
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.
Highlights
Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine tract in the mutant huntingtin protein
Huntington disease (HD) is a neurodegenerative, fatal trinucleotide repeat disorder caused by a CAG expansion in exon 1 of the huntingtin gene (HTT) yielding a mutant protein with a polyQ tract exceeding a pathogenic threshold of Q > ~351
Mutant huntingtin exon 1-Q51 filaments exhibit a large variation in width, narrow branching angles, and lamination
Summary
Huntington disease (HD) is a neurodegenerative trinucleotide repeat disorder caused by an expanded poly-glutamine (polyQ) tract in the mutant huntingtin (mHTT) protein. 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. Since structure often determines function[16], as shown for mHTT toxic aggregates[17,18], an increased structural understanding of polyQ aggregates can help uncover the mechanisms underlying their biogenesis, development, and cytotoxicity to better model polyQ disorders. Both small mHTT oligomers and large inclusion bodies can be neurotoxic[19,20]. A green fluorescence protein (GFP) fusion tag was used in the former, which can alter mEx1 aggregation[27], and detailed analyses of filament topologies were not pursued
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