Effect of retinoic acid receptor agonist on phosphorylated TDP-43, as a hallmark of Amyotrophic lateral sclerosis.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised primarily by muscle deterioration, atrophy, and respiratory failure, ultimately leading to death. Unfortunately, ALS lacks effective therapeutic options. A common pathological feature present in ALS cases is the hyperphosphorylation of TAR-DNA binding protein 43 (TDP-43), leading to the aggregation of phosphorylated TDP-43 in the cytoplasm. Retinoic acid receptor agonists are being studied for their potential neuroprotective effects, as indicated by numerous research studies. This particular study seeks to examine the effects of the retinoic acid receptor agonist DC645 on phosphorylated TDP-43 in the NSC-34 cell line, which might provide a novel treatment choice. Sodium arsenite at a concentration of 500 μM was used to induce stress in NSC-34 cells for 45 minutes, and the impact of 100 nm DC645 was assessed. Immunocytochemistry was conducted to analyse the expression and localisation of pTDP-43, followed by the use of western blotting for the semi-quantification of pTDP-43. Acute stress was associated with granular forms of pTDP-43, indicating a potential for aggregation, particularly in the nucleus, with and without the administration of the drug. Stress was also found to decrease the level of pTDP-43 on the blot, suggesting this reduction might be due to aggregation and loss of solubility of TDP-43. DC645 did not seem to inhibit the formation of pTDP-43 aggregation, and it might have even induced a pro-aggregation effect. Since this study only examined a limited number of samples, it needs to be replicated with a large number of samples, and further investigation of the effects of DC645 is warranted.