Cadherins in Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) are developmental disorders with a multiple genetic background. Many genes have been shown to be associated with ASD, including genes coding for cell-adhesion molecules. These molecules are important in developmental processes, such as brain development. Mutations in these genes coding for cell-adhesion molecules can lead to altered brain development and altered synapse formation causing ASD. The underlying mechanisms are largely unknown, however knowledge on the functions of cell-adhesion molecules suggests their implications in the development of ASD. A family of cell-adhesion molecules associated with ASD is the cadherin family. Cadherins are highly expressed in the central nervous system and involved in synapse formation. The cadherin family can be further divided in subfamilies based on their homology; classical cadherins (type I and type II), protocadherins (pcdh), seven-pass transmembrane cadherins and miscellaneous cadherins. The extracellular domain of cadherin contains a cadherin repeat sequence able to form dimers with other cadherin molecules across the synapse. Subtypes of the cadherin family have different intracellular domains, resulting in differences in signal transduction. Classical cadherins bind β-catenin and p120-catenin and interact with the actin cytoskeleton via α-catenin. Furthermore, they are cleaved by ADAM10, presenilin 1 and MT5-MMP, creating an intracellular domain that translocates to the nucleus and regulates gene transcription. Classical cadherins also interact with other receptors with common signalling molecules. Eight cadherin subtypes have been shown to be associated with ASD: cadherin 8, -9, -10, -15, and -18, and protocadherin 9, -10 and -19. Unfortunately, their roles in brain development and the development of ASD are largely unknown, but some functions are suggested in this thesis.