Because CYFIP1 is abundant at synapses (Figure S1), we immunoprecipitated CYFIP1 from mouse cortical synaptoneurosomes. Sixteen proteins were identified by MS, seven of which had not been detected in the cortical lysate data set likely because they are enriched in the CYFIP1 complexes in the synaptic compartment. The synaptic CYFIP1 interactome contained not only RBPs, but also cytoskeleton-related proteins, including components of the WRC (NCKAP1, ABI1/2, and WAVE1; Figure 6D; Tables S3 and S4). These results further demonstrate that CYFIP1 is active in regulating http://www.selleckchem.com/products/cx-5461.html mRNA translation and determining cytoskeleton-based cell morphology. Deletions

and duplications of a chromosomal region including CYFIP1 have been linked

CT99021 ic50 to ID, ASD, and schizophrenia ( Cooper et al., 2011, Doornbos et al., 2009, Leblond et al., 2012, Murthy et al., 2007, Nowicki et al., 2007, Tam et al., 2010, van der Zwaag et al., 2010, von der Lippe et al., 2010 and Zhao et al., 2012). We reasoned that proteins in the same protein network might have a similar pathological effect. A literature search on disease involvement of the genes in question revealed that 25 out of the 40 proteins that bind CYFIP1 are encoded by genes associated with ID, ASD, ADHD, schizophrenia, major depressive disorder, and Alzheimer’s disease ( Tables S4 and S5). In addition, a gene-based analysis interrogating for association with schizophrenia based on the meta-analytic p values obtained by the largest schizophrenia Farnesyltransferase genome-wide association study to date (

Ripke et al., 2011) (9,394 cases and 12,462 controls) revealed that 8 out of 36 tested autosomal genes of the CYFIP1 interactome had a nominally significant p value (<0.05) for association with schizophrenia ( Tables S4–S6). This significantly exceeds the expectation (1.8 genes) under the null hypothesis of no association (one-sided Fisher’s exact test, p = 0.042), although the polygenic nature of schizophrenia should be considered. One gene, FAM120A, was significantly associated with schizophrenia (p = 0.00064) after Bonferroni correction for testing 36 genes. In summary, 25 proteins out of 40 identified in our CYFIP1 interactome are encoded by genes involved in diseases: 26% are associated with schizophrenia, 19% with ASD, and 10% with ID ( Table S4; Figure 6E). These observations suggest that CYFIP1 and its interaction partners are linked to pathways that, if impaired, can be associated with intellectual disabilities and psychiatric disorders. CYFIP1 is present in two functional complexes essential for synaptic morphology and function: a ribonucleoparticle repressing protein synthesis and the WAVE regulatory complex (Figure 6F). When CYFIP1 interacts with NCKAP1 forming a platform for the assembly of the WRC, the interaction with eIF4E is obstructed and vice versa.