Recent reports suggest an important role for protein ubiquitination in synaptic plasticity. We cloned, from the rat brain, a novel gene that encoded an ubiquitin-specific protease (USP), and termed this protein synaptic ubiquitin-specific protease (synUSP, GenBankTM Accession no. AB073880). The homologous human gene was mapped to a locus on chromosome 1p36.12. The deduced synUSP protein consisted of 1036 amino acids, and possessed an ubiquitin-like domain at the C-terminus, Cys- and His-boxes, leucine zipper motifs, and six amino acid-repeats of L/ILCPHG. The protein possessed de-ubiquitinating activity toward a model substrate, as expected from its sequence. The protein of 125 kDa was present in the rat brain; in particular, it was enriched in the post-synaptic density and the dendritic lipid raft fractions. The immunostaining of cortical neurons confirmed the post-synaptic localization. The mRNA for synUSP was localized to dendrites, as well as somas, of neuronal cells. Thus, both the mRNA and the protein were localized in the post-synaptic compartments. These results suggest a regulatory mechanism for the ubiquitin-related system at the post-synaptic sites.