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.

Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration

“…Using this methodology, we have described that the progressive decrease in Drosophila locomotor activity during aging correlates with a physiological decrease in the expression of the TBPH protein, homologous to the human TDP-43 (15). Consistently, we and others showed that also in mice TDP-43 undergoes an aging-dependent decrease (15,16), highlighting the evolutionary relevance of this phenomenon. However, the relationships between these events have not been clarified yet.…”

“…One of the most fundamental features of aging is the progressive deterioration in locomotor skills. Despite some studies, in both mice and flies revealing that TDP-43/TBPH levels decrease during aging (15,16,38), the mechanism underlying aging-dependent locomotor [Type here] 9 senescence and the accompanying physiological decrease of TDP-43 is unclear. Likewise, it is not obvious whether the lowering of TDP-43 levels leads to a locomotor decline in the elderly.…”

“…Thus, to determine if the downregulation of TBPH during Drosophila aging is related to changes in the methylation patterns of H3K9, we performed chromatin immunoprecipitation (ChIP) studies and assessed the binding profile of H3K9me3 on the TBPH promoter. Remarkably, we found a significant enrichment in H3K9me3 amounts sited on the TBPH promoter in chromatin samples extracted from old flies compared to young controls (Figure 2A), revealing an increase in the levels of repressive heterochromatin modifications on the TBPH promoter in vivo during [Type here] 6 aging (16,30,31). In support of this observation, we noted that these epigenetic changes do not appear to be due to a generalized and/or nonspecific increase in H3K9 methylation caused by age, as its overall biochemical levels appear to decrease in old brains (Supplementary Figure S2), suggesting that the modifications described on the TBPH promoter are rather specific and may promote transcriptional repression of this gene.…”

“…In support of this view, we and others have described that defects in the conserved TDP-43 (encoded by the TARDBP gene), a member of the heterogeneous nuclear ribonucleoproteins (hnRNPs) family and largely associated with the pathogenesis of ALS (10)(11)(12), is permanently required in the nervous system to maintain locomotor activity and becomes downregulated during aging in Drosophila and mammalian brains (13)(14)(15)(16). Moreover, TDP-43 tight regulation in humans is required also in other tissues (such as glia and skeletal muscles) to maintain the correct molecular organization of the neuromuscular synapses and muscular innervation, all aspects critical for the motor system functioning (17)(18)(19)(20)(21).…”

Splicing accuracy varies across human introns, tissues and age

“…Previous studies have reported an overall reduction in the expression of multiple RBPs with increasing age [55][56][57][58][59][60][61] . We formally assessed this in the GTEx data set and, focusing on brain tissue, found that the expression levels of 20.7% of the 116 RBPs studied were negatively affected by age (1.1e-07<q<4.2e-02) (Methods, Supplementary Table 6).…”