A Comprehensive Atlas of E3 Ubiquitin Ligase Mutations in Neurological Disorders

Abstract

Protein ubiquitination is a posttranslational modification that plays an integral part in mediating diverse cellular functions. The process of protein ubiquitination requires an enzymatic cascade that consists of a ubiquitin activating enzyme (E1), ubiquitin conjugating enzyme (E2) and an E3 ubiquitin ligase (E3). There are an estimated 600-700 E3 ligase genes representing ~5% of the human genome. Not surprisingly, mutations in E3 ligase genes have been observed in multiple neurological conditions. We constructed a comprehensive atlas of disrupted E3 ligase genes in common (CND) and rare neurological diseases (RND). Of the predicted and known human E3 ligase genes, we found ~13% were mutated in a neurological disorder with 83 total genes representing 70 different types of neurological diseases. Of the E3 ligase genes identified, 51 were associated with an RND. Here, we provide an updated list of neurological disorders associated with E3 ligase gene disruption. We further highlight research in these neurological disorders and discuss the advanced technologies used to support these findings.

Keywords: angelman syndrome; neurological; rare diseases; transgenic; ubiquitin.

Figure 1

Common neurological disorders (CNDs) and E3 ligase gene associations. Diagram of CNDs correlated with E3 ligase genes that are mutated in specific disorders. Diseases shaded in blue indicate multiple genes linked to that disorder. Genes highlighted in dark gray are shared between several diseases. Figures were generated using Graphviz (www.graphviz.org).

Figure 2

Common neurological disorders (CNDs) and their associated E3 ligase domain type. CNDs that contain mutations in E3 ligase domains (blue). Diseases such as schizophrenia and Alzheimer's disease accompany mutations in different types of E3 ligases. Figures were generated using Graphviz (www.graphviz.org).

Figure 3

Rare neurological disorders (RNDs) and E3 ligase gene associations. Diagram of RNDs correlated with E3 ligase genes that are mutated in specific disorders. Diseases shaded in blue indicate multiple genes linked to that disorder. Genes highlighted in dark gray are shared between several diseases. Figures were generated using Graphviz (www.graphviz.org).

Figure 4

Rare neurological disorders (RNDs) and their associated E3 ligase domain type. RNDs that contain mutations in E3 ligase domains (blue). RING domain-containing E3 ligases account for ~53% of known mutated E3 ligase genes in RNDs. Figures were generated using Graphviz (www.graphviz.org).

Figure 5

Characteristic features of gene mutations in Ube3a observed in Angelman syndrome. Angelman syndrome mouse models show abnormal sleep patterns that are accompanied by EEG recordings displaying increased delta power and dynamic delta oscillations; mouse strain-dependent seizures; learning impairments including intellectual disability and developmental delay. Specific symptoms vary in individual cases. In AS mouse models, maternal deletion of Ube3a causes microcephaly and leads to multiple deficits in synaptic plasticity such as decreased LTP induction, deficits in mGluR-dependent LTD and homeostatic scaling. Mutations in UBE3A alter neuronal morphology that includes decreased axon caliber and spine density, and increased spine elimination in select brain regions.