Functional dissection of SLITRK1 signaling

Abstract

Background and aims

Tourette syndrome (TS) is a neuropsychiatric disorder characterized by motor and vocal tics and associated complex behavioral abnormalities. There is strong support for a genetic basis to the disorder, however, the precise pattern of transmission and the identification of underlying genes has remained elusive. Recently, mutations in a gene termed SLIT- and NTRK-like family, member 1 (SLITRK1) have been shown to lead to rare forms of TS and associated disorders. The SLITRK family (SLITRK 1-6) includes neuronal transmembrane proteins that can control neurite outgrowth. Structurally, SLITRK family members are characterized by two leucine-rich repeat (LRR) domains located on the extracellular/intralumenal domain, a single transmembrane domain, and an intracellular/cytoplasmic domain that is of varying lengths. SLITRK1 has a cytoplasmic domain that is most different from the others, being both the shortest (53 amino acids), and lacking conserved potential sites of tyrosine phosphorylation. We are using molecular methods to dissect SLITRK1 signaling and metabolism.

Methods

We developed a bait from the human SLITRK1 protein and used it to screen libraries for SLITRK1-interacting proteins. In addition, we studied the metabolism of SLITRK1 in situ.

Results

We completed screens of both an adult and a fetal brain library and are characterizing the validated SLITRK1-interacting proteins. We have also characterized SLITRK1 metabolism and the effects of SLITRk1 mutations on its metabolism.

Conclusions

SLITRK1-interacting proteins may represent susceptibility loci for TS and related disorders, and are likely involved in the development of the central nervous system.