The correct folding of newly synthesized proteins is regulated by a pathway that involves heat-shock proteins and chaperonins, such as TRiC (also known as CCT). Three groups have identified a new substrate for TRiC — Huntingtin (HTT) — and show that TRiC can direct HTT away from forming the toxic aggregates that characterize the devastating pathology of Huntington's disease.

TRiC is a cytoplasmic protein that is made up of two rings of eight homologous subunits, stacked back-to-back, that form a cage in which the normal folding reactions of many proteins have been shown to occur. Kitamura et al., as well as the other two groups, show that overexpression of TRiC can prevent the formation of mutant-HTT aggregates when it is expressed in yeast cells, mammalian cell lines and neuronal cells. In all cases, this was associated with reduced cell death. Mutant HTT still oligomerizes in the presence of TRiC, but it forms aggregates with different properties that do not seem detrimental to cell survival.

Behrends and colleagues investigated a possible cooperative function of TRiC with a second protein that is involved in regulating protein folding — heat-shock protein-70 (HSP70). They found that the protective function of TRiC depended on the presence of HSP70, and that TRiC could only act on HTT after it had been processed by HSP70. This fits with the well known role of these proteins in normal protein regulation: HSP70 interacts first at the point of translation to prevent premature folding events, whereas TRiC functions downstream to regulate the correct folding and aggregation of proteins.

Previous work has shown that TRiC specifically prevents the aggregation of newly synthesized proteins by recognizing hydrophobic β-strands. Interestingly, toxic conformations of mutant HTT adopt a β-sheet structure, thereby providing a glimpse of how TRiC might recognize and regulate the conformation of HTT.

Tam et al. investigated the effect of overexpressing each of the eight subunits of TRiC. Whereas most subunits did not prevent the formation of cellular inclusions, subunit-1 strongly inhibited toxic HTT aggregation and increased neuron viability. This protective activity was found to reside in the apical domain of the protein, which has been recently shown to contain the protein's polypeptide-binding site. However, RNA knockdown of just one of the other eight subunits was enough to stimulate HTT aggregation and neuronal toxicity, which, instead, indicates that only the fully assembled TRiC chaperonin complex can provide neuroprotection against mutant HTT.

So, it seems that mutant HTT can oligomerize by mechanisms that can lead to the formation of either toxic or benign aggregates. If the findings of Tam et al. — that part of subunit-1 is sufficient to promote a non-toxic HTT-aggregation pathway — can be verified, then small peptide inhibitors, modelled on the TRiC binding site, might serve as effective therapies against Huntington's disease.