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

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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.