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TitleStructural insight into transmissive mutant huntingtin species by correlative light and electron microscopy and cryo-electron tomography.
Journal, issue, pagesBiochem Biophys Res Commun, Vol. 560, Page 99-9104, Year 2021
Publish dateJun 30, 2021
AuthorsXuyuan Kuang / Kyle Nunn / Jennifer Jiang / Paul Castellano / Uttara Hardikar / Arianna Horgan / Joyce Kong / Zhiqun Tan / Wei Dai /
PubMed AbstractAggregates 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 ...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.
External linksBiochem Biophys Res Commun / PubMed:33984771 / PubMed Central
MethodsEM (tomography)
Structure data

EMDB-23737: PolyQ40 oligomer tomogram at 2uM concentration
Method: EM (tomography)

EMDB-23756: Tomogram of conditioned medium generated from PC12 14A2.6 cells showing mHTT assemblies
Method: EM (tomography)

EMDB-23762: Tomogram of preformed liposomes incubated with polyQ40 oligomers at 2uM concentration
Method: EM (tomography)

EMDB-23768: Tomogram of conditioned medium generated from PC12 14A2.6 cells showing mHTT assemblies (uncoated)
Method: EM (tomography)

Source
  • Homo sapiens (human)
  • Rattus norvegicus (Norway rat)

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