Structural insight into transmissive mutant huntingtin species by correlative light and electron microscopy and cryo-electron tomography

Xuyuan Kuang, Kyle Nunn, Jennifer Jiang, Paul Castellano, Uttara Hardikar, Arianna Horgan, Joyce Kong, Zhiqun Tan, Wei Dai

Research output: Contribution to journalArticlepeer-review

Abstract

Aggregates of mutant huntingtin (mHTT) containing an expanded polyglutamine (polyQ) tract are hallmarks of Huntington's Disease (HD). Studies have shown that mHTT can spread between cells, leading to the propagation of misfolded protein pathology. However, the structure of transmissive mHTT species, and the molecular mechanisms underlying their transmission remain unknown. Using correlative light and electron microscopy (CLEM) and cryo-electron tomography (cryo-ET), we identified two types of aggregation-prone granules in conditioned medium from PC12 cells expressing a mHTT N-terminal fragment: densities enclosed by extracellular vesicles (EVs), and uncoated, amorphous meshworks of heterogeneous oligomers that co-localize with clusters of EVs. In vitro assays confirmed that liposomes induce condensation of polyQ oligomers into higher-order assemblies, resembling the uncoated meshworks observed in PC12 conditioned medium. Our findings provide novel insights into formation and architecture of transmissive mHTT proteins, and highlight the potential role of EVs as both carriers and modulators of transmissive mHTT proteins.

Original languageEnglish (US)
Pages (from-to)99-104
Number of pages6
JournalBiochemical and Biophysical Research Communications
Volume560
DOIs
StatePublished - Jun 30 2021

ASJC Scopus subject areas

  • Biophysics
  • Biochemistry
  • Molecular Biology
  • Cell Biology

Keywords

  • Cryo-electron tomography
  • Extracellular vesicles
  • Mutant huntingtin
  • Protein transmission

Fingerprint

Dive into the research topics of 'Structural insight into transmissive mutant huntingtin species by correlative light and electron microscopy and cryo-electron tomography'. Together they form a unique fingerprint.

Cite this