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.

Disruption of histone acetylation-mediated gene control is a critical step in Alzheimer's Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin (ChIP-seq) and transcriptional (RNA-seq) profiling study in Drosophila melanogaster brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes. Moreover, AD brains exhibit robust genome-wide early alterations that include enhanced HDAC2 and reduced Tip60 binding and transcriptional dysregulation. Orthologous human genes to co-Tip60/HDAC2 D. melanogaster neural targets exhibit conserved disruption patterns in AD patient hippocampi. Notably, we discovered distinct transcription factor binding sites close or within Tip60/HDAC2 co-peaks in neuronal genes, implicating them in coenzyme recruitment. Increased Tip60 protects against transcriptional dysregulation and enhanced HDAC2 enrichment genome-wide. We advocate Tip60 HAT/HDAC2 mediated epigenetic neuronal gene disruption as a genome-wide initial causal event in AD.

IntroductionGlutamate excitotoxicity is causal in striatal neurodegeneration underlying motor dysfunction and cognitive deficits in Huntington’s disease (HD). Excitatory amino acid transporter 2 (EAAT2), the predominant glutamate transporter accounting for >90% of glutamate transport, plays a key role in preventing excitotoxicity by clearing excess glutamate from the intrasynaptic cleft. Accordingly, EAAT2 has emerged as a promising therapeutic target for prevention of neuronal excitotoxicity underlying HD and other neurodegenerative diseases.MethodsWe have previously designed novel EAAT2 positive allosteric modulator GT951, GTS467, and GTS551, with low nanomolar efficacy in glutamate uptake and favorable pharmacokinetic properties. In this study, we test the neuroprotective abilities of these novel EAAT2 activators in vivo using the robust Drosophila HD transgenic model expressing human huntingtin gene with expanded repeats (Htt128Q).ResultsAll three compounds significantly restored motor function impaired under HD pathology over a wide dose range. Additionally, treatment with all three compounds significantly improved HD-associated olfactory associative learning and short-term memory defects, while GT951 and GTS551 also improved middle-term memory in low-performing group. Similarly, treatment with GT951 and GTS551 partially protected against early mortality observed in our HD model. Further, treatment with all three EAAT2 activators induced epigenetic expression of EAAT2 Drosophila homolog and several cognition-associated genes.ConclusionTogether, these results highlight the efficacy of GT951, GTS467 and GTS551 in treating motor and cognitive impairments under HD pathology and support their development for treatment of HD.

Disruption of histone acetylation mediated gene control is a critical step in Alzheimer's Disease (AD), yet chromatin analysis of antagonistic histone acetyltransferases (HATs) and histone deacetylases (HDACs) causing these alterations remains uncharacterized. We report the first Tip60 HAT versus HDAC2 chromatin and transcriptional profiling study in Drosophila brains that model early human AD. We find Tip60 and HDAC2 predominantly recruited to identical neuronal genes. Moreover, AD brains exhibit robust genome-wide early alterations that include enhanced HDAC2 and reduced Tip60 binding and transcriptional dysregulation. Orthologous human genes to co-Tip60/HDAC2 Drosophila neural targets exhibit conserved disruption patterns in AD patient hippocampi. Notably, we discovered distinct transcription factor (TF) binding sites within Tip60/HDAC2 co-peaks in neuronal genes, implicating them in co-enzyme recruitment. Increased Tip60 protects against transcriptional dysregulation and enhanced HDAC2 enrichment genome-wide. We advocate Tip60 HAT/HDAC2 mediated epigenetic neuronal gene disruption as a genome-wide initial causal event in AD.