Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases

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.

Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain

“…Further, these Tip60/HDAC2 binding alterations at specific gene loci are present before Aβ accumulation is detectable, supporting these sites as potentially valuable early AD biomarker 'hot spots' that are easy to track. Recently, we reported that disruption of Tip60 and HDAC2 balance in the brain is a common event in other neurodegenerative diseases modelled in D. melanogaster: Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease [44]. Further studies may reveal a therapeutic potential for targeting Tip60 in these disorders as well.…”

Ontology Specific Alternative Splicing Changes in Alzheimer’s Disease

“…Kat5 is a major histone acetyltransferase that plays important roles in the regulation of DNA repair, autophagy, proteasome-dependent protein turnover, and learning and memory. Disruption of Kat5 mediated histone acetylation was an early common event in neurodegenerative disorders including AD ( Beaver et al, 2020 ; Li and Rasmussen, 2020 ).…”

“…Most retained introns were degraded by the NMD pathway due to the premature termination codons in the newly formed transcript. However, some mRNAs may bypass NMD and be translated ( Beaver et al, 2020 ; Li and Rasmussen, 2020 ). Li HD et al performed integrative functional genomic analysis of RI in AD and observed remarkable correlations of RI transcripts within innate immune genes.…”

Chromatin and transcriptomic profiling uncover dysregulation of the Tip60 HAT/HDAC2 epigenomic landscape in the neurodegenerative brain

“…Further, these Tip60/HDAC2 binding alterations, at specific gene loci, before Aβ accumulation is detectable, support these sites as potentially valuable early AD biomarker “hot spots” that are easy to track. Recently, we reported that disruption of Tip60 and HDAC2 balance in the brain is a common event in other neurodegenerative diseases modeled in Drosophila : HD, ALS, and PD (Beaver et al, 2020). Further studies may reveal a therapeutic potential for targeting Tip60 in these disorders as well.…”