Roles and mechanisms of ankyrin-G in neuropsychiatric disorders

• Published in: Experimental & molecular medicine 2022, 54(0), , pp.1-11
• Main Authors: Yoon, Sehyoun, Piguel, Nicolas H., Penzes, Peter
• Format: Article
• Language: English
• Subjects: 45/43; 631/337/458/1733; 631/378/340; Ankyrins; Autism; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Cell adhesion; Dendritic spines; Developmental stages; Isoforms; Localization; Medical Biochemistry; Mental disorders; Molecular Medicine; Mutation; Neurodevelopmental disorders; Nodes of Ranvier; Proteins; Review; Review Article; Schizophrenia; Stem Cells; Synapses; 생화학
• ISSN: 2092-6413; 1226-3613; 2092-6413
• DOI: 10.1038/s12276-022-00798-w

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. Neuropsychiatry: Potential roles of a scaffolding protein Mutations affecting the production, distribution, or function of the ankyrin-G protein may contribute to a variety of different neuropsychiatric disorders. Ankyrin-G is typically observed at the synapses between neurons, and contributes to intercellular adhesion and signaling along with other important functions. Peter Penzes and colleagues at Northwestern University, Chicago, USA, review the biology of this protein and identify potential mechanisms by which ankyrin-G mutations might impair healthy brain development. Mutations in the gene encoding this protein are strongly linked with bipolar disorder, but have also been tentatively connected to autism spectrum disorders and schizophrenia. The authors highlight physiologically important interactions with a diverse array of other brain proteins, which can in turn be modulated by various chemical modifications to ankyrin-G, and conclude that drugs that influence these modifications could have potential therapeutic value.