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

The ubiquitin pathway, one of the main actors regulating cell signaling processes and cellular protein homeostasis, is directly involved in the pathophysiology of amyotrophic lateral sclerosis (ALS). We first analyzed, by a next-generation sequencing (NGS) strategy, a series of genes of the ubiquitin pathway in two cohorts of familial and sporadic ALS patients comprising 176 ALS patients. We identified several pathogenic variants in different genes of this ubiquitin pathway already described in ALS, such as FUS, CCNF and UBQLN2. Other variants of interest were discovered in new genes studied in this disease, in particular in the HECW1 gene. We have shown that the HECT E3 ligase called NEDL1, encoded by the HECW1 gene, is expressed in neurons, mainly in their somas. Its overexpression is associated with increased cell death in vitro and, very interestingly, with the cytoplasmic mislocalization of TDP-43, a major protein involved in ALS. These results give new support for the role of the ubiquitin pathway in ALS, and suggest further studies of the HECW1 gene and its protein NEDL1 in the pathophysiology of ALS.

Automated summary

Using next-generation sequencing, pathogenic variants in genes of the ubiquitin pathway were identified in ALS patients, including known genes FUS, CCNF, and UBQLN2, as well as new genes such as HECW1. Overexpression of NEDL1, a protein encoded by HECW1, was found to be associated with increased cell death and mislocalization of TDP-43. These findings provide further evidence for the involvement of the ubiquitin pathway in ALS and suggest the need for further investigation of the HECW1 gene and NEDL1 in ALS pathophysiology.