alpha-Synuclein has been implicated in the pathogenesis of Parkinson's disease. The function of alpha-synuclein has not been deciphered yet; however, it might play a role in vesicle function, transport, or as a chaperone. alpha-Synuclein belongs to a family of three proteins, which includes beta- and gamma-synuclein. gamma-Synuclein shares 60% similarity with alpha-synuclein. Similar to alpha-synuclein, a physiological function for gamma-synuclein has not been defined yet, but it has been implicated in tumorgenesis and neurodegeneration. Interestingly, neither alpha- (SNCA(-/-)), gamma- (SNCG(-/-)), nor alpha/gamma- (SNCA_G(-/-)) deficient mice are present with any obvious phenotype. Using microarray analysis, we thus investigated whether deficiency of alpha- and gamma-synuclein leads to similar compensatory mechanisms at the RNA level and whether similar transcriptional signatures are altered in the brain. Sixty-five genes were differentially expressed in all mice. SNCA(-/-) mice and SNCG(-/-) mice shared 84 differentially expressed genes, SNCA(-/-) and SNCA_G(-/-) expressed 79 genes, and SNCG(-/-) and SNCA_G(-/-) expressed 148 genes. For many of the physiological pathways such as dopamine receptor signaling (down-regulated), cellular development, nervous system function, and cell death (up-regulated), we found groups of genes that were similarly altered in SNCA(-/-) and SNCG(-/-) mice. In one of the pathways altered in both models, we found Mapk1 as the core transcript. Other gene groups, however, such as TGF-beta signaling and apoptosis pathways genes were significantly up-regulated in the SNCA(-/-) mice but down-regulated in SNCG(-/-) mice. beta-synuclein expression was not significantly altered in any of the models.