Down syndrome is mainly Caused by a trisomy of chromosome 21. The Down syndrome critical region 2 (DSCR2) gene is located within a part of chromosome 21, the Down syndrome critical region (DSCR). To investigate the function of DSCR2, we Sought to identify DSCR2-interacting proteins using yeast two-hybrid assays. A human fetal brain cDNA library was screened, and DSCR2 was found to interact With a member of the nuclear receptor superfamily, peroxisome proliferator-activated receptor beta, (PPAR beta). A co-immunoprecipitation assay demonstrated that DSCR2 physically interacts with PPAR beta in mammalian HEK293 cells. DSCR2 also inhibited the ligand-induced transcriptional activity of PPAR beta. Furthermore, PPAR beta also decreased the solubility of DSCR2, which increased levels of insoluble DSCR2. (c) 2008 Elsevier Inc. All rights reserved.