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.

How to Inactivate Human Ubiquitin E3 Ligases by Mutation

“…Mutations on E3 ligases have been associated with a number of diseases, including neurological disorders (George et al, 2018;Osinalde et al, 2019). Thus, understanding their mechanism of action, as well as identifying which substrates are regulated by each E3 at different developmental stages and cell types, will provide invaluable knowledge that might contribute to develop therapeutic strategies to treat these diseases.…”

Non‐syndromic X linked intellectual disability: Current knowledge in light of the recent advances in molecular and functional studies

“…Ubiquitination has recently been recognized as a biological process of interest in the field of ID because some authors have reported its implication in neurological disorders that include neurodegenerative and neurodevelopmental disorders . Ubiquitination is a post‐translational modification that involves the addition of a small polypeptide called ubiquitin to target proteins.…”

“…HUWE1 (OMIM *300697) encodes a HECT type E3 ligase and it is known to regulate neural differentiation and proliferation through poly‐ubiquitination of specific target proteins like MYCN, p53 and CDC6 for subsequent proteasomal degradation . HUWE1 is known to be critical in development, because its loss leads to embryonic lethality in mice .…”

Impaired proteostasis in rare neurological diseases

“…The E1 enzyme UBA1 is implicated in the aetiology of X-linked infantile spinal muscular atrophy (XL-SMA) [83], and mutations in the E2 enzyme UBE2A result in UBE2A deficiency syndrome [84], whereas the E2 enzyme UBE2K, which can catalyse protein ubiquitination independent of E3 ligases, is a pivotal factor modulating the neurotoxicity of expanded huntingtin in Huntington's disease [85]. Additionally, more than 10 distinct RNDs are also known to be originated as a consequence of defective HECT-type E3 ligases [82,101]. The vast majority of RNDs caused by E3s are due to mutations either reducing or disrupting the activity of the ubiquitin ligases, therefore resulting in impaired ubiquitination of their substrates.…”

“…The U-box domain containing E3 ligase CHIP can cause SCAR16 [103] and is also involved in Gordon Holmes syndrome, a rare neurodegenerative disorder characterized by hypogonadism and ataxia [82]. This disease can also be caused by the combination of mutations in the RING-finger type E3 ligase RNF216 [88] and consequently, astrocytes suffer many molecular changes, including proteasome inhibition [75].…”