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

Abstract

TDP-43 cellular levels are tightly regulated, increases, or decreases in these have deleterious effects in cells. The predominant mechanism responsible for regulation of the TDP-43 levels 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 levels 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 levels lower than those needed by the cell and thereby triggers the onset of symptoms.