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 and 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.

Study of Ubiquitin Pathway Genes in a French Population with Amyotrophic Lateral Sclerosis: Focus on HECW1 Encoding the E3 Ligase NEDL1

“…Functional studies are needed to better understand this HECW1 gene and the functions of the E3 ligase NEDL1 in order to perhaps reclassify the previous variants. NEDL1 is a member of the NEDD4 subfamily that contains nine members, sharing common domains [ 9 ]. One target of NEDL1 ligase action could be the receptor tyrosine kinase ErbB4, which is mutated in some ALS cases [ 22 , 23 ].…”

“…These E3 enzymes are classified into two major families, the E3 RING ligases and the E3 HECT ligases. Each of these families contains enzymes playing important roles in mechanisms involved in neurodevelopment and neurodegeneration, such as the NEDD4 subfamily of HECT E3 ligases, several members of which have been implicated in the pathophysiology of neurodegenerative diseases [ 8 , 9 ]. The ubiquitin pathway also involves other proteins required for its function.…”

Alu Deletions in LAMA2 and CDH4 Genes Are Key Components of Polygenic Predictors of Longevity

“…This protein is abundant in neuronal tissues such as brain and spinal cord [ 54 ]. Thus, due to its participation in protein homeostasis, HECW1 is a key element in the normal and pathological development of nervous system [ 55 ]. The HECW1 gene product controls the cell cycle through the enhancement of the transcriptional and pro-apoptotic activity of p53 [ 56 ].…”

Unraveling the Potential Role of NEDD4-like E3 Ligases in Cancer

“…The proteins NEDD4 and NEDD4-2 were the first members of this subfamily to be found and are now the most investigated. The subfamily members are considered to be involved in a variety of illnesses, including cancer and neurological diseases [ 60 , 70 ].…”

“…Its dual role in cancer is frequently studied, as it can serve both as a tumor suppressor and an oncoprotein [ 83 ]. NEDL1 and NEDL2 are also known as the HECT, C2, and WW domains containing E3 ubiquitin–protein ligase 1 (HECW1) and 2 (HECW2) [ 70 ]. By ubiquitinating and degrading Dishevelled-1(Dvl1), NEDL1 participates in the Wnt signaling pathway [ 84 , 85 ].…”