Structural insight in how TRiC chaperonin inhibits mutant huntingtin aggregation

What is it about?

In Huntington’s disease, a mutated version of the huntingtin protein leads to cell death. Mutant huntingtin (mhtt) is known to aggregate, a process that can be inhibited by the eukaryotic chaperonin TRiC (TCP1-ring complex). Here, we characterize the growth of fibrillar aggregates of mhtt, and we resolve 3-D structures of the chaperonin TRiC interacting with mhtt. We find that TRiC caps mhtt fibril tips, and encapsulates mhtt smaller oligomers within its chamber.

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Why is it important?

We use special microscopy at cryo-temperatures to preserve these specimens in a frozen-hydrated, physiologically-relevant state. Our data reveals two complementary mechanisms by which the TRiC chaperonin inhibits mutant huntingtin (mhtt) aggregation in vitro. We also show mhtt aggregation at nanoscale, both in the absence and presence of TRiC. Such structural understanding of the genesis of aggregates and their modulation by cellular chaperones can lead toward developing novel therapies.