The world population is aging rapidly, and increasing lifespan exacerbates the burden of age-related health issues. On the other hand, premature aging has begun to be a problem, with increasing numbers of younger people suffering aging-related symptoms. Advanced aging is caused by a combination of factors: lifestyle, diet, external and internal factors, as well as oxidative stress (OS). Although OS is the most researched aging factor, it is also the least understood. OS is important not only in relation to aging but also due to its strong impact on neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), Alzheimer’s disease (AD), and Parkinson’s disease (PD). In this review, we will discuss the aging process in relation to OS, the function of OS in neurodegenerative disorders, and prospective therapeutics capable of relieving neurodegenerative symptoms associated with the pro-oxidative condition.

The pathological hallmark of the majority of amyotrophic lateral sclerosis (ALS) cases is the mislocalization and aggregation of TAR DNA-binding protein 43 (TDP-43), an RNA-binding protein. Several studies have attributed disease processes of ALS to abnormal RNA metabolism. However, dysregulated biogenesis of RNA, especially non-coding RNA (ncRNA), is poorly understood. To resolve it, RNA-Seq, biochemical, and immunohistochemical analyses were performed on the pyramidal tract of the medulla oblongata of sporadic ALS (sALS) and control postmortem brain samples. Here, we report perturbation of ncRNA biogenesis in PIWI-interacting RNA (piRNA) in several sALS brain samples associated with TDP-43 pathology. In addition, we confirmed the dysregulation of two PIWI homologs, PIWI-like-mediated gene silencing 1 (PIWIL1) and PIWIL4, which bind to piRNAs to regulate their expression. PIWIL1 was mislocalized and co-localized with TDP-43 in motor neurons of sporadic ALS lumbar cords. Our results imply that dysregulation of piRNA, PIWIL1, and PIWIL4 is linked to pathogenesis of ALS. Based on these results, piRNAs and PIWI proteins are potential diagnostic biomarkers and therapeutic targets of ALS.

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.

Background: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder, with its currently approved drugs, including riluzole and edaravone, showing limited therapeutic effects. Therefore, safe and effective drugs are urgently necessary. EPI-589 is an orally available, small-molecule, novel redox-active agent characterized by highly potent protective effects against oxidative stress with high blood-brain barrier permeability. Given the apparent oxidative stress and mitochondrial dysfunction involvement in the pathogenesis of ALS, EPI-589 may hold promise as a therapeutic agent. Objective: This protocol aims to describe the design and rationale for the EPI-589 Early Phase 2 Investigator-Initiated Clinical Trial for ALS (EPIC-ALS). Methods: EPIC-ALS is an explorative, open-labeled, single-arm trial that evaluates the safety and tolerability of EPI-589 in patients with ALS. This trial consists of 12-week run-in, 24-week treatment, and 4-week follow-up periods. Patients will receive 500 mg of EPI-589 3 times daily over the 24-week treatment period. Clinical assessments include the mean monthly change of Amyotrophic Lateral Sclerosis Functional Rating Scale–Revised total score. The biomarkers are selected to analyze the effect on oxidative stress and neuronal damage. The plasma biomarkers are 8-hydroxy-2′-deoxyguanosine (8-OHdG), 3-nitrotyrosine (3-NT), neurofilament light chain (NfL), phosphorylated neurofilament heavy chain (pNfH), homocysteine, and creatinine. The cerebrospinal fluid biomarkers are 8-OHdG, 3-NT, NfL, pNfH, and ornithine. The magnetic resonance biomarkers are fractional anisotropy in the corticospinal tract and N-acetylaspartate in the primary motor area. Results: This trial began data collection in September 2021 and is expected to be completed in October 2023. Conclusions: This study can provide useful data to understand the characteristics of EPI-589. Trial Registration: Japan Primary Registries Network jRCT2061210031; tinyurl.com/2p84emu6 International Registered Report Identifier (IRRID): DERR1-10.2196/42032

Amyotrophic lateral sclerosis (ALS) is characterized by the mislocalization and abnormal deposition of TAR DNA-binding protein 43 (TDP-43). This protein plays important roles in RNA metabolism and transport in motor neurons and glial cells. In addition, abnormal iron accumulation and oxidative stress are observed in the brain and spinal cord of patients with ALS exhibiting TDP-43 pathology and in animal models of ALS. We have previously demonstrated that TDP-43 downregulation significantly affects the expression of ferritin heavy chain (Fth1) mRNA in the axonal regions of neurons. Nevertheless, the mechanisms by which TDP-43 contributes to oxidative stress and iron accumulation in the central nervous system remain elusive. In this study, we aimed to investigate whether Fth1 mRNA is a target transported to the axon by TDP-43 using biophysical and biochemical analyses. Our results revealed Fth1 mRNA as a target mRNA transported to axons by TDP-43. Moreover, we demonstrated that TDP-43 regulates iron homeostasis and oxidative stress in neurons via Fth1 mRNA transport to the axons, possibly followed by a local translation of the ferritin heavy chain in the axons. This study suggests that TDP-43 plays an important role in preventing iron-mediated oxidative stress in neurons, with its loss contributing to ALS pathogenesis.