The Roles of NEDD4 Subfamily of HECT E3 Ubiquitin Ligases in Neurodevelopment and Neurodegeneration

Abstract

The ubiquitin pathway regulates the function of many proteins and controls cellular protein homeostasis. In recent years, it has attracted great interest in neurodevelopmental and neurodegenerative diseases. Here, we have presented the first review on the roles of the 9 proteins of the HECT E3 ligase NEDD4 subfamily in the development and function of neurons in the central nervous system (CNS). We discussed their regulation and their direct or indirect involvement in neurodevelopmental diseases, such as intellectual disability, and neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease or Amyotrophic Lateral Sclerosis. Further studies on the roles of these proteins, their regulation and their targets in neurons will certainly contribute to a better understanding of neuronal function and dysfunction, and will also provide interesting information for the development of therapeutics targeting them.

Keywords: ALS; development; intellectual disability; ligases; neurodegenerative; ubiquitin.

Figure 1

Schematic representation of ubiquitination process by E3 ligases containing HECT domain. Ubiquitin is activated by an enzyme E1 and then transferred to E2 enzymes, and to a HECT E3 enzyme. The E3 enzyme transfers ubiquitin to the target protein, leading to its monoubiquitination or polyubiquitination. The E3 ligase contains 3 domains, an N-terminal C2 domain, a WW rich domain and a C-terminal domain organized into two lobes (N-lobe and C-lobe).

Figure 2

Structure of the 9 HECT E3 ligases of the NEDD4 subfamily. Protein size and domain conservation expressed as percentage of conservation compared to NEDD4.1 protein. Sequence of the nine members (UniprotKB) and identity percentage are obtained by alignment (MUSCLE) for the C2 and the HECT domains. Blue boxes represent the WW domains of each protein. Due to differences in the number of WW domains across proteins, identity percentage is not calculated for these domains.

Figure 3

Schematic representation of the roles played by E3 ligases of the HECT subfamily in cellular processes involved in CNS development and neurodegeneration. Substrates of these enzymes are presented in the references.