Physiological tissue-specific and age-related reduction of mouse TDP-43 levels is regulated by epigenetic modifications

The cellular level of TDP-43 (also known as TARDBP) is tightly regulated; increases or decreases in TDP-43 have deleterious effects in cells. The predominant mechanism responsible for the regulation of the level of TDP-43 is an autoregulatory negative feedback loop. In this study, we identified an in vivo cause-effect relationship between Tardbp gene promoter methylation and specific histone modification and the TDP-43 level in tissues of mice at two different ages. Furthermore, epigenetic control was observed in mouse and human cultured cell lines. In amyotrophic lateral sclerosis, the formation of TDP-43-containing brain inclusions removes functional protein from the system. This phenomenon is continuous but compensated by newly synthesized protein. The balance between sequestration and new synthesis might become critical with ageing, if accompanied by an epigenetic modification-regulated decrease in newly synthesized TDP-43. Sequestration by aggregates would then decrease the amount of functional TDP-43 to a level lower than those needed by the cell and thereby trigger the onset of symptoms.

Automated summary

The regulation of TDP-43 levels is tightly controlled by a negative autoregulatory loop, with epigenetic modifications influencing the protein levels in different tissues and cell lines. In conditions like amyotrophic lateral sclerosis, where TDP-43-containing aggregates sequester functional protein, the balance between sequestration and new synthesis becomes crucial for cellular function, especially in aging.