Abstract
Epigenetic dysregulation is a common mechanism shared by molecularly and clinically heterogenous neurodegenerative diseases (NDs). Histone acetylation homeostasis, maintained by the antagonistic activity of histone acetyltransferases (HATs) and histone deacetylases (HDACs), is necessary for appropriate gene expression and neuronal function. Disruption of neural acetylation homeostasis has been implicated in multiple types of NDs including Alzheimer’s disease (AD), yet mechanisms underlying alterations remain unclear. We show that like AD, disruption of Tip60 HAT/HDAC2 balance with concomitant epigenetic repression of common Tip60 target neuroplasticity genes occurs early in multiple types of Drosophila ND models such as Parkinson’s Disease (PD), Huntington’s Disease (HD) and Amyotrophic Lateral Sclerosis (ALS). Repressed neuroplasticity genes show reduced enrichment of Tip60 and epigentic acetylation signatures at all gene loci examined with certain genes showing inappropriate HDAC2 repressor enrichment. Functional neuronal consequences for these disease conditions are reminiscent of human pathology and include locomotion, synapse morphology, and short-term memory deficits. Increasing Tip60 HAT levels specifically in the mushroom body learning and memory center in the Drosophila brain protects against locomotion and short-term memory function deficits in multiple NDs. Together, our results support a model by which Tip60 protects against neurological impairments in different NDs via similar modes of action.
Highlights
Epigenetic dysregulation is a common mechanism shared by molecularly and clinically heterogenous neurodegenerative diseases (NDs)
We further demonstrated that increasing Tip[60] levels in the Alzheimer’s disease (AD) Drosophila brain protects against alteration of Tip[60] histone acetyltransferases (HATs)/HDAC2 balance, epigeneticmediated neuroplasticity gene repression and functional cognitive deficits that occur during early stages of neurodegenerative progression[17]
We show that disruption of Tip[60] HAT/HDAC2 balance with concomitant epigenetic repression of common neuroplasticity Tip[60] 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)
Summary
Epigenetic dysregulation is a common mechanism shared by molecularly and clinically heterogenous neurodegenerative diseases (NDs). We further demonstrated that increasing Tip[60] levels in the AD Drosophila brain protects against alteration of Tip[60] HAT/HDAC2 balance, epigeneticmediated neuroplasticity gene repression and functional cognitive deficits that occur during early stages of neurodegenerative progression[17]. We test the hypothesis that Tip[60] mediated histone acetylation homeostasis is disrupted during early stages of neurodegeneration in multiple types of NDs. We show that disruption of Tip[60] HAT/HDAC2 balance with concomitant epigenetic repression of common neuroplasticity Tip[60] 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). Our findings are the first to demonstrate that disruption of Tip[60] HAT/HDAC2 homeostasis and concomitant Tip[60] gene control is a critical initial mechanism common to multiple neurodegenerative disorders
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