Seminar

Abstract

Aging is a complex process characterized by the decline of biological functions and the increased susceptibility to both genetic and sporadic neurodegenerative diseases. However, the interrelationship
between the aging process and disease-causing genes is still unknown. It has been proposed that aging-associated epigenetic alterations may modify the expression of disease-causing genes affecting neuronal
survival. 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
expression levels of this gene through an epigenetic mechanism 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, improving motility parameters in old flies.
The data uncover a novel role of this enzyme in regulating TDP-43 expression and locomotor senescence and indicate conserved epigenetic mechanisms that may play a role in the pathogenesis of ALS and in aging-associated disorders.