52 Fmr1 knockout mice confirm the global upregulation of transcripts. In FXS, synaptic transcript products upregulate through FMRP’s failure to recruit CYFIP1, a cytoplasmic FMRl-interacting protein that is also a eukaryotic

translation initiation factor 4E (eIF4E) binding protein. Interestingly, loss of FMRP in both mice and humans results in abnormal dendritic spine morphology, a Inhibitors,research,lifescience,medical characteristic of many intellectual disability-associated disorders. Case studies of nonsyndromic forms of autism have identified de novo variants in genes involved in translational control. Of note, eIF4E is downstream of several of these signaling pathways, and mutations directly in eIF4E have been discovered in three autistic individuals.53 This study found de novo

gene disruptions in 14 autism candidate genes and 13 CNVs that overlapped with FMRP target genes,30 which supports the notion that FXS-associated autistic phenotypes may result from disrupted expression levels of specific gene products. It is hypothesized that disrupted protein translation may lead to abnormal neuronal Inhibitors,research,lifescience,medical morphology and, hence, abnormal synaptogenesis. This faulty brain connectivity may be responsible for the global impairment in learning and memory associated with disorders of intellectual disability like FXS. However, comorbid autism in these disorders could reflect a disruption of the same developmental mechanism but perhaps of more specialized Inhibitors,research,lifescience,medical circuits or synapses responsible for social learning. Inhibitors,research,lifescience,medical Many candidate genes for ASD pathology map onto the endosomal pathway.54 A family of protein exchangers localized on endosomes have recently been studied in syndromic autism. Christiansen syndrome, which presents like Angelman syndrome, has been associated with the functional loss of the endosomal Na+/H+ exchanger NHE6 (also known as SLC9A6).55,56 Many cases of nonsyndromic autism have been linked to deficits in cellular trafficking of proteins57; an autistic individual with a chromosomal

inversion Inhibitors,research,lifescience,medical that disrupts receptor expression-enhancing protein 3 (REEP3), a putative regulator of vesicle trafficking between the ER and Golgi http://www.selleckchem.com/products/ABT-888.html network58; two individuals with mutations in the small GTPase RAB39B and an individual with a haploinsufficiency of the small GTPase RAB39B59; Megestrol Acetate a translocation that disrupts the NEUROBEACHIN (NBEA) gene.58 This evidence suggests mostly GTPases and their regulators of the recycling endosomes at the presynapse are affecting the transport of specific cargo. A recent study reported that collapse of the recycling endosome results in a decrease in spine density in an activity-dependent manner.61 We can predict how mutations in genes involved in protein trafficking can directly affect neurite morphogenesis and synaptogenesis. Cellular trafficking of proteins is also indirectly critical for membrane dynamics underlying mechanisms of synaptic plasticity and neurotransmission.