We show that disruption of Tip60 HAT/HDAC2 balance with concomitant epigenetic repression of common neuroplasticity Tip60 target genes is an early event in multiple types of Drosophila ND models that include Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Here, TMPRSS11D is linked to juvenile Huntington disease.