Alternative Splicing Alterations in Patients With Amyotrophic Lateral Sclerosis: Link to the Disruption of TAR DNA-Binding Protein 43 kDa Functions

Abstract

Background: Amyotrophic lateral sclerosis (ALS) is a neuromuscular disease that causes degeneration of both upper and lower motor neurons. TAR DNA-binding protein 43 kDa (TDP-43) is mislocalized in the motor neurons of patients with ALS. TDP-43 regulates RNA metabolism, including alternative splicing. Although the dysregulation of alternative splicing by TDP-43 is supposed to have a key role in ALS pathology, the nature of aberrant alternative splicing in the tissues of patients with ALS has not been well studied. Aim: To screen for alternative splicing alterations in patients with ALS to find those linked to ALS pathology. Methods: Postmortem human tissue samples were collected from brain banks and subjected to RNA sequencing and polymerase chain reaction analyses. Results: We identified 16 novel genes that exhibited significant splicing changes. In addition, in TDP-43-deficient SH-SY5Y cells, five genes exhibited similar splicing patterns, indicating that a part of the altered alternative splicing in patients is regulated by TDP-43. Conclusion: Although further studies on the pathological significance of these splicing changes are needed, they have the potential to serve as therapeutic targets for the treatment of ALS.