Human genetics:
Drawn into bad company

from Nature Reviews Genetics

Magdalena Skipper

Polyglutamine (polyQ) repeat expansions are involved in several human disorders, perhaps the most famous among them being Huntington disease (HD). The HD gene was cloned in 1993, and subsequently, much effort has gone into the molecular characterization of the disease. Two significant new strides in this direction have just been made — Schaffar et al. show that transcription factors drawn into the bad company of mutant huntingtin (HTT) cannot bind their DNA targets, whereas Choo et al. find that HTT associates with the mitochondrial outer membrane and that mutant HTT alters mitochondrial permeability.

Expanded tracts of polyQ might cause disease through negative interactions with the ubiquitin–proteasome system or with important proteins, such as TATA-box-binding proteins (TBP) and transcriptional co-activator CREB-binding proteins (CBP), which also contain polyQ repeats. Schaffar et al. used an in vitro system, mouse neuroblastoma cells and a yeast model to focus on the second hypothesis.

By using a combination of mutant and wild-type HTT and TBP with or without polyQ tracts, they showed that TBP binds to HTT only when the polyQ tracts are present. Not surprisingly, aggregated TBPs cannot bind their targets. Mutant HTT can exert this toxic effect on transcription factors even before the formation of the multiprotein aggregates, which are also known as inclusion bodies and which are a hallmark of the disease at the cellular level. The authors also show in vitro and in mouse neuroblastoma cells that insoluble pre-existing aggregates of HTT cannot interact with TBP; only the newly synthesized, soluble HTT can.

PolyQ only becomes toxic after a conformational change in mutant HTT— Schaffar et al. show that the non-toxic glutathione S–transferase (GST)-tagged HTT becomes toxic when the GST is cleaved off. Drawing a parallel with the in vivo situation, they suggest that similar to the GST tag in the experimental setting, the rest of the HTT protein shields the polyQ repeats from adopting the toxic conformation. They propose that this shielding process might account for the late onset of the disease.

The late onset of the disease might also involve HSP70/HSP40 chaperones, which also prevent HTT polyQ tracts from adopting the toxic conformation. These chaperones might also protect polyQ tracts on other proteins, such as TBPs, and so prevent the formation of complexes between these proteins and HTT. The authors suggest that as age takes its toll on the efficiency of the chaperone system, the symptoms of disease begin to appear.

HD has also been associated with mitochondrial dysfunction and this aspect of the disease was the focus of the study by Choo et al. Not only is the wild-type and mutant HTT associated with the outer mitochondrial membrane, but, as the authors show in a mouse knock-in HD model, expanded polyQ tract causes mitochondrial membranes to become leaky, leading to what is known as mitochondrial permeability transition — an important contributor to apoptosis and necrosis.

The gene that is responsible for HD was cloned more than 10 years ago and although we still do not know what HTT function actually is, we are coming ever closer to understanding the mechanisms by which expanded polyQ repeats cause this and other polyQ-associated diseases.

References

ORIGINAL RESEARCH PAPERS Schaffar, G. et al. Cellular toxicity of polyglutamine expansion proteins: mechanism of transcription factor deactivation. Mol. Cell 15, 95–105 (2004) Choo, Y. S. et al. Mutant huntigtin directly increases susceptibility of mitochondria to the calcium-induced permeability transition and cytochrome c release. Hum. Mol. Genet. 13, 1407–1420 (2004)