A HAT for sleep?

Tip off the HAT– Epigenetic control of learning and memory byDrosophilaTip60

“…45 We previously demonstrated that Tip60 HAT action is critical for nervous system development and cognitive processes such as synaptic plasticity, axonal outgrowth and transport via its transcriptional regulation of genes enriched for a variety of specific neuronal processes. 40 Consistent with a role for Tip60 in nervous system function, our laboratory 7,17,30,34,[40][41][42][43][44]46 and others 7,30,[47][48][49][50] have shown that the HAT Tip60 is implicated in Alzheimer's disease (AD) based on its role in epigenetic neuronal gene control via its formation of a transcriptionally active complex with the processed C-terminal amyloid precursor protein (APP) intracellular domain (AICD). 30,43,47,48,[51][52][53][54][55][56][57] Loss of Tip60 HAT activity and/or improper recruitment of this complex to specific gene promoters causes epigenetic misregulation of a variety of genes causatively associated with neurodegeneratation.…”

“…7,17,30,34,[40][41][42][43][44] While Tip60 was shown to be the second highest expressed HAT of the 18 HATs in mammalian adult brain, its involvement in neural function was unknown. 45 We previously demonstrated that Tip60 HAT action is critical for nervous system development and cognitive processes such as synaptic plasticity, axonal outgrowth and transport via its transcriptional regulation of genes enriched for a variety of specific neuronal processes.…”

“…30,43,47,50,51 During the past several years, my laboratory has published a compendium of studies characterizing a functional interaction between Tip60 and the APP-C terminus (AICD) in mediating multiple cognitive neuronal processes using Tip60; APP transgenic Drosophila we generated as a robust model system. 7,17,30,34,[40][41][42][43] To develop this system, we utilized well characterized APP Drosophila lines that express equivalent and moderate levels of either GAL 4 responsive full length human APP (hAPP695) or APP lacking the AICD domain (APP-dCT) 43,58,59 and adapted them to harbor our GAL4 responsive Drosophila Tip60 wild-type (Tip60 WT ) or dominant negative HAT mutant (Tip60 E431Q ) transgenes. 40,43,46 This Tip60;APP Drosophila system enables us to modulate controlled Tip60 HAT levels in specific neural circuits in the fly of choice under APP induced neurodegenerative conditions, in vivo.…”

“…40,43,46 Using this model, we demonstrated that a number of cognition linked processes known to be impaired during early AD neuropathology that include neuronal apoptosis, axonal outgrowth and transport are mediated via a functional interaction between Tip60 and AICD. We also made the exciting discovery that increasing in vivo Tip60 HAT levels in the Drosophila nervous system under APP induced neurodegenerative conditions rescues AD associated neuronal impairments such as apoptotic neurodegeneration in the central nervous system (CNS), 43 axonal outgrowth 41,42 and synaptic vesicle transport in motor neurons. 30 Excess Tip60 also restores associated disrupted complex functional abilities impaired in AD that include sleep cycles 41,42 and locomotor function 30 with concomitant induction of genes critical for the function of these neural processes.…”

“…We also made the exciting discovery that increasing in vivo Tip60 HAT levels in the Drosophila nervous system under APP induced neurodegenerative conditions rescues AD associated neuronal impairments such as apoptotic neurodegeneration in the central nervous system (CNS), 43 axonal outgrowth 41,42 and synaptic vesicle transport in motor neurons. 30 Excess Tip60 also restores associated disrupted complex functional abilities impaired in AD that include sleep cycles 41,42 and locomotor function 30 with concomitant induction of genes critical for the function of these neural processes. 30,43 In direct contrast, loss of Tip60 HAT function in the fly nervous system causes gene misregulation and exacerbates such AD associated impaired phenoytpes.…”