An Autism-Causing Variant Misregulates Selective Autophagy to Alter Axon Targeting and Behavior

Abstract

Neurodevelopmental disorders cause debilitating disruptions to the cellular mechanisms that underlie development of the brain. Unfortunately, the complexities of neurodevelopmental disorders make them difficult to study, and the molecular mechanisms perturbed by these disorders remain elusive. Better understanding of neurodevelopmental mechanisms, and the related genes involved, will likely yield new insight into neurodevelopmental disorders. A gene that has been associated with a number of neurodevelopmental disorders is the calcium voltage-gated channel subunit alpha1 C (CACNA1C) gene. Common and rare variants of the CACNA1C gene have been associated with autism and other neurodevelopmental disorders including schizophrenia, bipolar disorder and ADHD. However, little is known about how CACNA1C variants affect cellular processes to alter neurodevelopment. The Timothy syndrome mutation is a rare, gain-of-function variant in CACNA1C that causes autism with high penetrance, providing a powerful avenue into investigating the role of CACNA1C variants in neurodevelopmental disorders. A gain-of-function (gof) mutation in the C. elegans CACNA1C homolog known as egl-19 causes an equivalent amino acid change to the Timothy syndrome mutation in humans. This work shows that this egl-19(gof) mutation can alter axon targeting and affect behavior in C. elegans. Wildtype egl-19 functions independently of Regulator of Presynaptic Morphology-1 (rpm-1) to negatively regulate axon termination. The egl-19(gof) mutation represses axon termination to cause axon targeting defects that lead to the misplacement of electrical synapses and alterations in habituation to light touch. Moreover, genetic analysis indicates that selective autophagy acts downstream of the egl-19(gof) mutation to mediate its effects on both axon termination and behavior. These results reveal a novel mechanism whereby an autism-causing variant of CACNA1C misregulates selective autophagy to alter circuit formation and affect behavior.