By the two hybrid screening of mouse brain cDNA library, we identified Hppi, a cell death-promoting protein, as a binding partner of postsynaptic scaffold protein Homeric. Hippi interacted specifically with Homeric but not with its homologue Homer2. It was reported that Hippi, when complexed with Hip], induces the apoptosis in striatal neurons and may cause Huntington's disease. We found that this apoptotic effect of Hippi was specific to the striatum and was not observed in hippocampal neurons. Furthermore, the apoptotic effect of Hippi was prevented when Homeric was co-expressed in cultured striatal neurons. The protective effect of Homeric was diminished when Hippi binding domain was deleted. These results suggest that Homeric may play an important role in the mechanisms of neuronal death in the striatum. (c) 2006 Elsevier Inc. All rights reserved.