Roles and mechanisms of ankyrin-G in neuropsychiatric disorders

Abstract

Ankyrin proteins act as molecular scaffolds and play an essential role in regulating cellular functions. Recent evidence has implicated the ANK3 gene, encoding ankyrin-G, in bipolar disorder (BD), schizophrenia (SZ), and autism spectrum disorder (ASD). Within neurons, ankyrin-G plays an important role in localizing proteins to the axon initial segment and nodes of Ranvier or to the dendritic shaft and spines. In this review, we describe the expression patterns of ankyrin-G isoforms, which vary according to the stage of brain development, and consider their functional differences. Furthermore, we discuss how posttranslational modifications of ankyrin-G affect its protein expression, interactions, and subcellular localization. Understanding these mechanisms leads us to elucidate potential pathways of pathogenesis in neurodevelopmental and psychiatric disorders, including BD, SZ, and ASD, which are caused by rare pathogenic mutations or changes in the expression levels of ankyrin-G in the brain.

Fig. 1. Psychiatric risk factors include ankyrin proteins.

a Cytoscape analysis of the protein–protein interaction (PPI) network of psychiatric risk genes from GWAS and SFARI and ANKRD-containing proteins retrieved from UniProt and STRING. The large circular nodes indicate psychiatric risk genes, and edge thickness represents the connection score of the connected proteins (0.400 < score < 1.000). *p < 0.05; hypergeometry test (edited from Yoon et al.). b Enrichment of SZ risk factors (n = 395) (top), BD risk factors (n = 155) (bottom) identified through GWAS and ASD risk factors (n = 1003) (center) from SFARI among the PPI network of ankyrin-G from STRING (n = 200). ***p < 0.001; hypergeometry test. c The representative majority of a subnetwork is visualized and annotated by Cytoscape. The color-coded nodes indicate the score factor (0.100 < score < 1.000). SFARI Simons Foundation Autism Research Initiative; STRING Search Tool for the Retrieval of Interacting Genes/Proteins.

Fig. 2. Spatiotemporal expression of different isoforms of ANK3 in the brain.

a A diagram of ANK3 transcription start sites and alternative splicing. b Expression patterns of the ANK3 gene in the human brain (adapted from The Human Protein Atlas). c A schematic summary of the trajectories of the different ankyrin-G isoforms in the mouse brain. Expression levels were measured as log₁₀ of western blot intensities from Yoshimura et al..

Fig. 3. Posttranslational regulation of ankyrin-G and structure-dependent ankyrin-G binding partners.

Ankyrin-G forms four distinct domains: an ankyrin-repeat domain (ANKRD), a spectrin-binding domain, a regulatory domain that includes a death domain (DD), and a C-terminal domain (CTD). Each domain interacts with distinct ion channels, transporters, cell adhesion proteins and signaling molecules, and cytoskeletal elements. *: PSD proteins.

Fig. 4. A schematic model of the interacting partners of ankyrin-G, drawn with BioRender.

The model shows the interacting partners of ankyrin-G regulated by phosphorylation.