National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
NS092525
米国
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)
P41GM103832
米国
引用
ジャーナル: Commun Biol / 年: 2021 タイトル: Cryo-electron tomography provides topological insights into mutant huntingtin exon 1 and polyQ aggregates. 著者: Jesús G Galaz-Montoya / Sarah H Shahmoradian / Koning Shen / Judith Frydman / Wah Chiu / 要旨: 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 ...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.