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Disruption of Tip60 HAT mediated neural histone acetylation homeostasis is an early common event in neurodegenerative diseases
Journal article   Open access   Peer reviewed

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

Mariah Beaver, Akanksha Bhatnagar, Priyalakshmi Panikker, Haolin Zhang, Renee Snook, Visha Parmar, Gayathri Vijayakumar, Niteesha Betini, Sunya Akhter and Felice Elefant
Scientific reports, v 10(1), 18265
26 Oct 2020
DOI: https://doi.org/10.1038/s41598-020-75035-3
PMID: 33106538
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://doi.org/10.1038/s41598-020-75035-3View
Published, Version of Record (VoR)CC BY V4.0,  Open

Abstract

Acetylation Alzheimer Disease - metabolism Alzheimer Disease - pathology Animals Brain - metabolism Disease Models, Animal Drosophila Drosophila Proteins - metabolism Histone Acetyltransferases - metabolism Histones - chemistry Histones - metabolism Homeostasis Learning - physiology Memory - physiology Neurodegenerative Diseases - metabolism Neurodegenerative Diseases - pathology Parkinson Disease - metabolism Parkinson Disease - pathology
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.

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Web of Science research areas
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