Role of the Neuronal Splicing Factor A2BP1/RBFOX1 in Autism Spectrum Disorders

ASDs are among the most heritable neuropsychiatric conditions, and at the same time genetically very heterogeneous, with hundreds of genetic loci implicated in the disease (Voineagu 2012). Given the genetic heterogeneity of ASD, a challenging yet fundamental question is whether the wide variety of genetic changes ultimately dysregulate a common set of molecular pathways, amenable as therapeutic targets.

We recently demonstrated that despite genetic heterogeneity, shared abnormalities of gene expression could be detected in postmortem brain tissue from ASD cases (Voineagu et al. 2011). A key finding of this study was that the neuronal splicing factor A2BP1 (Ataxin-2 binding protein 1) was downregulated in a large subset of ASD brains. While A2BP1 has been previously implicated in ASD, the mechanisms of its transcriptional dysregulation and the functional consequences of altered A2BP1-dependent splicing in ASD remain unknown.

This project aims to:
(a) identify the genetic and epigenetic causes of A2BP1 transcriptional dysregulation in ASD brain;
(b) elucidate A2BP1-dependent alternative splicing targets in the human brain; and
(c) investigate the cellular and transcriptional consequences of A2BP1 dysfunction.

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