An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior


Autoři: Tyler Buddell aff001;  Vladislav Friedman aff001;  Cody J. Drozd aff001;  Christopher C. Quinn aff001
Působiště autorů: Department of Biological Sciences, University of Wisconsin-Milwaukee; Milwaukee, Wisconsin, United States of America aff001
Vyšlo v časopise: An autism-causing calcium channel variant functions with selective autophagy to alter axon targeting and behavior. PLoS Genet 15(12): e32767. doi:10.1371/journal.pgen.1008488
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008488

Souhrn

Common and rare variants of the CACNA1C voltage-gated calcium channel 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 de novo 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. Here, we use egl-19, the C. elegans homolog of CACNA1C, to investigate the role of voltage-gated calcium channels in autism. We show that an egl-19(gof) mutation that is equivalent to the Timothy syndrome mutation can alter axon targeting and affect behavior in C. elegans. We find that wildtype egl-19 negatively regulates 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 interactions indicate that the egl-19(gof) mutation functions with genes that promote selective autophagy to cause defects in axon termination and behavior. These results reveal a novel genetic mechanism whereby a de novo mutation in CACNA1C can drive alterations in circuit formation and behavior.

Klíčová slova:

Article-level metrics – Autism – Autophagic cell death – Axons – Electrical synapses – Mutation – Neurons – Genetic interactions


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