Journal article
Increasing Tip60 HAT Levels Rescues Axonal Transport Defects and Associated Behavioral Phenotypes in a Drosophila Alzheimer's Disease Model
The Journal of neuroscience, v 33(17), pp 7535-7547
24 Apr 2013
PMID: 23616558
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Axonal transport defects and axonopathy are prominent in early preclinical stages of Alzheimer's disease (AD), often preceding known disease-related pathology by over a year. As epigenetic transcriptional regulatory mechanisms, such as histone acetylation, are critical for neurogenesis, it is postulated that their misregulation might be linked to early pathophysiological mechanisms that contribute to AD. The histone acetyltransferase (HAT) Tip60 epigenetically regulates genes enriched for neuronal functions and is implicated in AD via its formation of a transcriptional regulatory complex with the amyloid precursor protein (APP) intracellular domain. Disruption of APP function is associated with axonal transport defects, raising the possibility that an epigenetic role for Tip60 might also be involved. Here, we examine whether Tip60 HAT activity functions in axonal transport using Drosophila CNS motor neurons as a well-characterized transport model. We show that reduction of Tip60 HAT activity in the nervous system causes axonopathy and transport defects associated with epigenetic misregulation of certain axonal transport-linked Tip60 target genes. Functional consequences of these defects are evidenced by reduced locomotion activity of the mutant Tip60 larvae, and these phenotypes can be partially rescued with certain histone deacetylase inhibitors. Finally, we demonstrate that Tip60 function in axonal transport is mediated by APP and that, remarkably, excess Tip60 exerts a neuroprotective role in APP-induced axonal transport and functional locomotion defects. Our observations highlight a novel functional interactive role between Tip60 HAT activity and APP in axonal transport and provide insight into the importance of specific HAT modulators for cognitive disorder treatment.
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Details
- Title
- Increasing Tip60 HAT Levels Rescues Axonal Transport Defects and Associated Behavioral Phenotypes in a Drosophila Alzheimer's Disease Model
- Creators
- Ashley A. Johnson - Drexel UniversityJessica Sarthi - Drexel UniversitySheila K. Pirooznia - Drexel UniversityWilliam Reube - Drexel UniversityFelice Elefant - Drexel University
- Publication Details
- The Journal of neuroscience, v 33(17), pp 7535-7547
- Publisher
- Soc Neuroscience
- Number of pages
- 13
- 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)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Biology
- Web of Science ID
- WOS:000318419300038
- Scopus ID
- 2-s2.0-84876554957
- Other Identifier
- 991019168443204721
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- Web of Science research areas
- Neurosciences