Academic journal article Genetics

Epigenetic Regulation of Axonal Growth of Drosophila Pacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

Academic journal article Genetics

Epigenetic Regulation of Axonal Growth of Drosophila Pacemaker Cells by Histone Acetyltransferase Tip60 Controls Sleep

Article excerpt

ABSTRACT Tip60 is a histone acetyltransferase (HAT) enzyme that epigenetically regulates genes enriched for neuronal functions through interaction with the amyloid precursor protein (APP) intracellular domain. However, whether Tip60-mediated epigenetic dysregulation affects specific neuronal processes in vivo and contributes to neurodegeneration remains unclear. Here, we show that Tip60 HAT activity mediates axonal growth of the Drosophila pacemaker cells, termed "small ventrolateral neurons" (sLNvs), and their production of the neuropeptide pigment-dispersing factor (PDF) that functions to stabilize Drosophila sleep-wake cycles. Using genetic approaches, we show that loss of Tip60 HAT activity in the presence of the Alzheimer's disease-associated APP affects PDF expression and causes retraction of the sLNv synaptic arbor required for presynaptic release of PDF. Functional consequence of these effects is evidenced by disruption of the sleep-wake cycle in these flies. Notably, overexpression of Tip60 in conjunction with APP rescues these sleep-wake disturbances by inducing overelaboration of the sLNv synaptic terminals and increasing PDF levels, supporting a neuroprotective role for dTip60 in sLNv growth and function under APP-induced neurodegenerative conditions. Our findings reveal a novel mechanism for Tip60 mediated sleep-wake regulation via control of axonal growth and PDF levels within the sLNv-encompassing neural network and provide insight into epigenetic-based regulation of sleep disturbances observed in neurodegenerative diseases like Alzheimer's disease.

CHROMATIN remodeling through histone-tail acetylation is critical for epigenetic regulation of transcription and has been recently identified as an essential mechanism for normal cognitive function (Fischer et al. 2007). Altered levels of global histone acetylation have been observed in several in vivo models of neurodegenerative diseases and are thought to be involved in the pathogenesis of various memory-related disorders (Stilling and Fischer 2011) . Chromatin acetylation status can become impaired during the lifetime of neurons through loss of function of specific histone acetyltransferases (HATs) with negative consequences on neuronal function (Selvi et al. 2010). In this regard, the HAT Tip60 is a multifunctional enzyme involved in a variety of chromatin-mediated processes that include transcriptional regulation, apoptosis, and cell-cycle control, with recently reported roles in nervous system function (Sapountzi et al. 2006; Squatrito et al. 2006). Work from our laboratory demonstrated that Tip60 HAT activity is required for nervous system development via the transcriptional control of genes enriched for neuronal function (Lorbeck et al. 2011). We have also shown that Tip60 HAT activity controls synaptic plasticity and growth (Sarthi and Elefant 2011) as well as apoptosis in the developing Drosophila central nervous system (CNS) (Pirooznia et al. 2012). Consistent with our findings, studies have implicated Tip60 in pathogenesis associated with different neurodegenerative diseases. The interaction of Tip60 with ataxin 1 protein has been reported to contribute to cerebellar degeneration associated with spinocerebellar ataxia (SCA1), a neurodegenerative disease caused by polyglutamine tract expansion (Gehrking et al. 2011). Tip60 is also implicated in Alzheimer's disease (AD) via its formation of a transcriptionally active complex with the AD-associated amyloid precursor protein (APP) intracellular domain (AICD) (Cao and Sudhof 2001; Slomnicki and Lesniak 2008). This complex increases histone acetylation (Kim et al. 2004) and co-activates gene promoters linked to apoptosis and neurotoxicity associated with AD (Kinoshita et al. 2002). Additionally, misregulation of certain putative target genes of the Tip60/AICD complex has been linked to AD-related pathology (Baek et al. 2002; Hernandez et al. 2009). These findings support the concept that inappropriate Tip60/AICD complex formation and/or recruitment early in development may contribute or lead to AD pathology via epigenetic misregulation of target genes that have critical neuronal functions. …

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