The nervous system is connposed of hundreds of distinct cell types, each with unique morphology, connections, and gene expression. Importantly, perturbations in rare cell types, composing a small fraction of the entire brain, can result in devastating disorders afflicting the entire organism. For many disorders, the circuits and cells underlying the disease are unknown. Recent technical advances have driven an ongoing explosion of genome wide studies attempting to associate genetic polymorphisms with disorders of the CNS. Likewise, other technologies have dramatically reduced the cost of resequencing candidate genes to identify putative mutations. Still, the understanding of how polymorphisms in various genes can lead to a common disease is generally not understood. We have recently developed a methodology. Translating Ribosome Affinity Purification (TRAP), to isolate the complete suite of genes being employed by any particular cell type in the mammalian brain. Here, we apply this methodology to help bridge the gap between a polymorphism in a gene and a symptom in a disorder with two general approaches. First, when a cell type is suspected of being selectively vulnerable in a disorder, we can identify the suite of genes that are employed selectively in that particular cell type as potential disease candidates. Second, when there are many candidate genes known, we can analyze our cell-type specific translational profiles to determine if these various genes implicate a common cell type or circuit. For the first approach, we have isolated the complete translational profile of serotonergic neurons. As dysregulation of the serotonergic system has long been suspected to be involved in autism, we have tested the association between the serotonergic genes and autism in a large multiplex patient population. We found association with common variants in two genes, and identified a deleterious rare variant in one of these genes, the RNA binding protein BRUN0L6. We are now recapitulating this mutation in mice and testing for behaviors reminiscent of autism, as well as applying high-throughput sequencing to understand the consequence of this mutation on splicing and translation of RNA in vitro and in vivo.
The cellular etiology of CNS disorders is an area much in need of elucidation. Even if patients have a variety of different underlying genetic causes for a disease, if a common cellular mechanism can be identified, that provides a target for treatment strategies. The approach proposed here may have the potential to provide those cellular targets for treatments.
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