Journal article
Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition
The Journal of neuroscience, v 38(19), pp 4569-4583
09 May 2018
PMID: 29654189
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Cognitive decline is a debilitating hallmark during preclinical stages of Alzheimer's disease (AD), yet the causes remain unclear. Because histone acetylation homeostasis is critical for mediating epigenetic gene control throughout neuronal development, wepostulated that its misregulation contributes to cognitive impairment preceding AD pathology. Here, we show that disruption of Tip60 histone acetlytransferase (HAT)/histone deacetylase 2 (HDAC2) homeostasis occurs early in the brain of an AD-associated amyloid precursor protein (APP) Drosophila model and triggers epigenetic repression of neuroplasticity genes well before A beta plaques form in male and female larvae. Repressed genes display enhanced HDAC2 binding and reduced Tip60 and histone acetylation enrichment. Increasing Tip60 in the AD-associated APP brain restores Tip60 HAT/HDAC2 balance by decreasing HDAC2 levels, reverses neuroepigenetic alterations to activate synaptic plasticity genes, and reinstates brain morphology and cognition. Such Drosophila neuroplasticity gene epigenetic signatures are conserved in male and female mouse hippocampus and their expression and Tip60 function is compromised in hippocampus from AD patients. We suggest that Tip60 HAT/HDAC2-mediated epigenetic gene disruption is a critical initial step in AD that is reversed by restoring Tip60 in the brain.
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Details
- Title
- Restoring Tip60 HAT/HDAC2 Balance in the Neurodegenerative Brain Relieves Epigenetic Transcriptional Repression and Reinstates Cognition
- Creators
- Priyalakshmi Panikker - Drexel UniversitySong-Jun Xu - Drexel UniversityHaolin Zhang - Drexel UniversityJessica Sarthi - Drexel UniversityMariah Beaver - Drexel UniversityAvni Sheth - Drexel UniversitySunya Akhter - Drexel UniversityFelice Elefant - Drexel UniversityHua Zhang - Electrical and Computer Engineering
- Publication Details
- The Journal of neuroscience, v 38(19), pp 4569-4583
- Publisher
- Soc Neuroscience
- Number of pages
- 15
- Grant note
- R01HD057939 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01HD057939 / EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD) R01NS095799 / NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Neurological Disorders & Stroke (NINDS)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology; Electrical and Computer Engineering
- Web of Science ID
- WOS:000431765500012
- Scopus ID
- 2-s2.0-85051083973
- Other Identifier
- 991019173463604721
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- Web of Science research areas
- Neurosciences