Year: 2011
Type: article
Abstract: Amyotrophic lateral sclerosis (ALS) is characterized by a neuronal loss in the motor cortex, brainstem, and spinal cord that progresses over a 3 to 5 year period. Approximately 90% of cases are considered sporadic, while the other 10% of cases are familial.1 Extensive research has been conducted on the SOD1 (RefSeq NM_000454.4) gene after mutations were identified more than 17 years ago in 15% to 20% of familial ALS cases, as well as a small number of sporadic ALS cases in later reports.1 In the last 2 years, mutations in TARDBP, which encodes TAR DNA-binding protein 43 (TDP-43), and in FUS have been identified in both familial and sporadic ALS cases.2-4 Both genes encode for RNA/DNA binding proteins, are mainly localized in the nucleus, and are implicated in the regulation of RNA processing.5 Specifically, TDP-43 and FUS have been shown to be associated with other splicing factors and are believed to play a role in splicing regulation, as variation in their expression level influences the splicing of certain targets.5 Interestingly, mutant TDP-43 proteins identified in patients with ALS were recently reported to be more stable than wild-type TDP-43 and to display an enhanced interaction with fused in sarcoma (FUS) polypeptides.6 Particularly, it was reported that the FUS protein interacts more predominantly with mutant TDP-43, which display an increased half-life compared with wild-type TDP-43. The authors concluded on a note about the efforts needed to determine whether the increased association affects the RNA targets for TDP-43, FUS/translocated in liposarcoma protein, or both.6 Considering that abnormal RNA processing and splicing patterns are involved in neurodegenerative diseases1 and that variation in the RNA splicing of SOD1 can cause familial ALS by destabilizing the resulting protein,1 our aim was to assess if TARDBP and/or FUS ALS-predisposing mutations that are known to lead to the accumulation of TDP-43 or FUS aggregations in the cytoplasm also lead to aberrant SOD1 RNA splicing events, and to determine if SOD1 could be an RNA target for TDP-43, FUS, or both.
Source: Archives of Neurology
Institution: Université de Montréal
Language: English
Subfield: Clinical Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2038290575