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

Aging progressively modifies the physiological balance of the organism increasing susceptibility to both genetic and sporadic neurodegenerative diseases. These changes include epigenetic chromatin remodeling events that may modify gene transcription. However, how aging interconnects with disease-causing genes is not well known. Here, we found that Su(var)3-9 causes increased methylation of histone H3K9 in the promoter region of TDP-43, the most frequently altered factor in amyotrophic lateral sclerosis (ALS), affecting the mRNA and protein expression levels of this gene through epigenetic modifications in chromatin organization that appear to be conserved in aged Drosophila brains, mouse and human cells. Remarkably, augmented Su(var)3-9 activity causes a decrease in TDP-43 expression followed by early defects in locomotor activities. In contrast, decreasing Su(var)3-9 action promotes higher levels of TDP-43 expression and reinvigorates motility parameters in old flies, uncovering a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence. The data indicate how conserved epigenetic mechanisms may link aging with neuronal diseases and suggest that Su(var)3-9 may play a role in the pathogenesis of ALS.