RNA Binding Proteins in Complex Neurological Disease

Columbia University Health Sciences, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Many factors make genetically complex diseases complex. Classically they are defined as an interaction between multiple genetic variants and non-genetic factors. Progress in genome sequencing and within-species variation has generated much interest in identifying polygenic variants from human and model organisms, with some success. But one cannot lose sight of the importance of physiological complexity; even Mendelian variants can wreak havoc when operating in a complex biological system. For functional phenotypes, such as excitability disorders of the CNS, this concept is understudied. Epilepsy is genetically complex to be sure, but as the canonical excitability disorder of the brain it also serves as a leading example for approaching other, harder-to-crack functional disorders, such as autism and schizophrenia, that are also likely to have excito-pathology at their cores. Neuronal excitability is determined primarily by molecules, such as ion channels and transporters, neurotransmitter receptors, and synaptic proteins, controlling membrane potential and synaptic signaling in order to achieve an appropriate balance of excitation and inhibition. Although cis-variants in genes encoding these molecules can lead to specific phenotypes, trans-factors that regulate their expression must be critical for maintaining this balance at a higher, coordinated level. We previously identified and characterized hypomorphic and null genotypes in Celf4 (formerly known as Brunol4), encoding a brain-specific member of the BRUNO/CUGBP/CELF family of RNA binding proteins. Celf4 mutants have a complex seizure disorder and other neurological phenotypes, such as hyperactivity, mild obesity and abnormal social interaction. Very recently human CELF4 deficiency revealed these and additional symptoms, such as intellectual disability. In our initial funding period, we found that CELF4 is most tightly associated with very high-density RNA granule particles and targets a vast number of mRNAs in excitatory neurons. Many targets are involved in synaptic functions, and they tend to be dysregulated within neurons of mutant mice - in all directions, but with a tendency towards increased expression away from the cell body. These findings are consistent with a role for CELF4 in control translational silencing perhaps at local, subcellular levels. We also obtained evidence for CELF4 effects on intrinsic neuronal hyperexcitation, via increased expression of sodium channel Nav1.6, and system-wide dysregulation via impaired homeostatic plasticity presumably due to dysregulation of synaptic proteins. Our hypothesis is that the combination of such effects accounts for full-blown disease. In the next 5 years, our research will address two prevailing themes that work together to address this idea. The first addresses the pattern of CELF4 binding motifs within the 3'-UTR of target mRNAs, and the consequences of altering the motifs on mRNA abundance, localization and translation, both transcriptome-wide and for selected targets. The second theme uses in vivo mutagenesis to assess the contribution of individual targets to the multigenic etiology of complex neurological phenotypes.