N. NICHOLSON

Huntington disease (HD) is caused by mutations in the huntingtin gene. Mutant Huntingtin protein (Htt) with expanded polyglutamine repeats forms aggregates in diseased brains. It has been suggested that the selective loss of neurons from the brain striatum of patients with HD is caused by apoptotic death. But how does mutant Htt activate the apoptotic pathway? Don Nicholson and colleagues now propose an attractive model on p.95 of this issue. The key is in the regulation of the interaction of Htt with its partner Hip-1. Nicholson and colleagues identify another partner for Hip-1, Hippi. The picture shows immunostaining of Hippi (yellow) in cortical pyramidal neurons (red) of the mouse brain. They show that the interaction between Hip-1 and Htt on the one hand, and between Hip-1 and Hippi on the other, are mutually exclusive, and that Hip-1/Hippi complexes can activate caspases, the effector enzymes of apoptosis.

In the normal brain, Hip-1 interacts with Htt. But the affinity of Hip-1 for mutant Htt is much lower than its affinity for wild-type Htt. So in diseased brains, levels of the Hip-1/Hippi complex are relatively higher than the levels of the Hip-1/Htt complex. In addition, the authors also demonstrate that the proenzyme procaspase-8 is recruited to Hip-1/Hippi complexes. Interestingly, previous studies have shown that active caspase-8 localizes to aggregates of mutant Htt, and that overexpression of mutant Htt induces apoptosis in a caspase-8-dependent manner. Nicholson and colleagues now show that Hip-1 and Hippi cooperate to induce apoptosis in a caspase-8-dependent manner when transfected into primary neurons. So the model suggests that Hip-1 and Hippi induce dimerization, and thus activation, of procaspase-8, thereby initiating the apoptotic cascade.