Detail

Our research focus is to use the cutting edge tools of three-dimensional (3D) cryo-electron tomography (cryoET) and correlative light and electron microscopy (CLEM) to study the structures of macromolecular machinery in their cellular context. Structures of intracellular macromolecular complexes are usually heterogeneous and dynamic, relying largely on interactions with other cellular components.  Using cryoET to determine the structure of cellular machinery inside the cell avoids damage to the complexes during purification, captures snapshots of the complex in action, and provides information on cross-talk of the complexes with their cellular partners during biological processes. Our current research interests lie in structures and organization of protein aggregates in neuorodegenerative diseases, and 3D architecture of the diseased cells under misfolded protein aggregation stress. The disease model we build our story on is Huntington’s Disease.

Huntington's disease (HD) is an inherited neurodegenerative disease characterized by progressive motor, cognitive, and psychiatric deterioration. In HD neurons, the formation, abundance and persistence of mutant huntingtin (mHTT) aggregation species are correlated with neurodegeneration, however, the identity of toxic species and the structural basis for mHTT toxicity are not clear. Multiple cellular pathways have been implicated in the pathogenesis of HD, including protein homeostasis, calcium signaling, mitochondrial dysfunction, and vesicular transport and recycling. Our goal is to use cryoET to directly visualize mHTT and cellular components involved in these cellular pathways, and thus provide insights to HD pathogenesis and potential therapeutic targets.

Figure 1: Sectional and 3D annotated views of polyQ seeded mutant huntingtin-GFP aggregates in cell lysate reveal the short fibril (yellow), long fibril and bundle aggregate structures (magenta) as well as cellular vesicles (blue). 

Figure 2: A tomogram of a HD cell showing structures of cellular organelles under misfolded protein stress.