Active zone protein transport and autism

Project Leader: Stephan Sigrist e-mail

 

It is an emerging picture that cognitive diseases of the nervous system can be caused by rather subtle deficits in the developmental formation of presynaptic release sites (“active zones”). Human genetics identified mutations in the active zone protein Neurexin and its postsynaptic partner Neuroligin as associated with autism spectrum diseases (ASDs). In the last period we have been establishing genetic and cell-biological in vivo models for Neurexin and Neuroligin function at Drosophila glutamatergic synapses. We found that Neurexin physically and functionally cooperates with the multidomain protein Syd-1 to steer the formation of presynaptic active zones, and via interaction with Neuroligin controls assembly of postsynaptic glutamate receptors clusters. Both human Rim binding proteins gene loci have also been associated with ASD. We could show that the Drosophila homologue (DRBP) is a core active zone component, and crucial for its developmental formation. DRBP we found associated with the cargo adaptor APP-like protein interacting protein 1 (Aplip1), linking active zone scaffold proteins to axonal transport processes. We will continue to exploit the genetic models established (aplip1, DRBP, Nrx, Nlg) for the further characterization of ASD candidate mutations, which we isolate in a continuing collaboration with C4. Moreover, we seek to explore the crossroads between active zone assembly, axonal long-range transport and ASD mutations. Systematic biochemical analysis of active zone protein transport complexes should help to target additional ASD candidate loci. The study uses a complementary set of genetic, cell biological, live intravital and super-resolution imaging as well as ultrastructural and physiological analysis.