Ankyrins and neurological disease

Abstract

Ankyrins are scaffolding proteins widely expressed throughout the nervous system. Ankyrins recruit diverse membrane proteins, including ion channels and cell adhesion molecules, into specialized subcellular membrane domains. These domains are stabilized by ankyrins interacting with the spectrin cytoskeleton. Ankyrin genes are highly associated with a number of neurological disorders, including Alzheimer's disease, schizophrenia, autism spectrum disorders, and bipolar disorder. Here, we discuss ankyrin function and their role in neurological disease. We propose mutations in ankyrins contribute to disease through two primary mechanisms: 1) altered neuronal excitability by disrupting ion channel clustering at key excitable domains, and 2) altered neuronal connectivity via impaired stabilization of membrane proteins.

Figure 1.

(A) Schematic of subcellular ankyrins with domains and interactions; and list of key interactors for each ankyrin. (B) Primary ankyrin isoforms. AnkR has one main isoform, 200kDa. However, alternative splicing of AnkB results in two main isoforms: 220kDa, and 440kDa. Similarly, alternative splicing of AnkG results in three main isoforms: 190kDa, 270kDa, and 480kDa. The 270kDa isoform results from an in-frame splicing of the giant exon eliminating 1,900 amino acids (*asterisk). Apart from the giant exon present in some isoforms, all three ankyrins have a similar structure. A N-terminal membrane binding domain (MBD) consisting of 24 ANK repeats, a linker domain, a recently discovered extension of the spectrin binding domain (SBD) termed ExZZU thought to enhance ankyrin-spectrin binding affinities, the SBD also known as the ZZU domain due to its three parts (ZU5_N, ZU5_C, and UPA), the DEATH domain (DD), and a regulatory C-terminal tail. (C) Schematic of ankyrin localization in neurons. All three ankyrins are expressed in neurons; however, each one has a unique pattern of localization. AnkB (blue) is expressed throughout neurons, however in some, AnkR is co-localized with AnkB at the soma and proximal dendrites (yellow). Whereas AnkG (green) is found at the AIS and nodes of Ranvier. Insets show (1) immunolabeling of AnkR and AnkG in adult mouse cortical neurons; scale bar, 10µm; (2) MAP2 (white) labeling the somatodendritic domain, AnkB (blue) co-localized with MAP2 in the somatodendritic domain but is also present in the distal axon, and AnkG (green) labeling the AIS in vitro rat hippocampal neurons at DIV10 [modified from 12]; scale bar, 10µm; and (3) Schwann cell derived paranodal AnkB (red), and AnkG (green) at a node of Ranvier in mouse sciatic nerve [modified from 11]; scale bar, 1µm.