Monday, May 19, 2025
5/19/2025
The epigenome-metabolism nexus as a driver of circadian disruption in Alzheimer's disease - Altered circadian rhythms and sleep patterns are a hallmark of both aging and neurodegenerative diseases including Alzheimer’s disease (AD). Disruptions in circadian behaviors are observed at an early stage of AD and emerging evidence suggests that these might not simply be a symptom of disease, but could also contribute to pathogenesis. Notably, these disruptions in circadian behaviors are also observed in both aging Drosophila and in fly models of AD, indicating that Drosophila provides a genetically tractable model system in which to identify the conserved mechanisms underlying AD-associated circadian disruption. Circadian rhythms are controlled by a molecular clock that consists of a transcription-translation feedback loop that requires the rhythmic deposition of chromatin marks for its proper regulation. The deposition of these chromatin marks is mediated by enzymes that use key metabolic intermediates as substrate, providing a connection between the metabolic state of a cell and its epigenome. During aging, we and others have observed changes in the metabolic pathways that produce the donor molecule required for histone and DNA methylation, S-adenosylmethionine (SAM) – referred to as one-carbon metabolism. In the aging Drosophila head, we observe changes in one-carbon metabolism including an increase in levels of S-adenosylhomocysteine (SAH), which inhibits the activity of methyltransferases. Similar changes in SAM and SAH levels have been reported in clinical samples from AD patients, suggesting that these metabolic changes are a common feature of aging and neurodegenerative disease in both flies and humans. In both flies and mice, the circadian clock is necessary to prevent age-dependent retinal degeneration and neurodegeneration, suggesting that disruptions to circadian rhythms in AD could indeed contribute to pathogenesis. Here, we propose to expand our lab’s current aging studies into the context of AD by testing if AD, like aging, leads to changes in one-carbon metabolism that alter the methylation capacity of peripheral clock cells leading to epigenetic changes that disrupt circadian rhythms. Based on our preliminary data, we will focus on two enzymes that control the ratio of SAM to SAH in flies: Glycine N-methyltransferase (Gnmt) and Adenosylhomocysteinase (Ahcy). We propose that the changes in the SAM:SAH ratio observed in aging and in AD patients could be generated by increased expression of Gnmt, which is induced by inflammation, and/or by decreased activity of Ahcy, which is inhibited under exposure to oxidative stress. Notably, Gnmt plays a similar role in one-carbon metabolism to that of an enzyme that is also upregulated in the brains of AD patients: nicotinamide N-methyltransferase (NNMT). We will determine how AD-associated tau alters circadian gene expression, one-carbon metabolism, and histone methylation, and use genetic approaches to test if Gnmt, human NNMT, and Ahcy are necessary and/or sufficient to explain the impact of tau on circadian behavior. These studies will provide the basis for expanding our work on metabolism, epigenetics, and circadian behavior from the aging eye into the context of neurodegenerative disease with a particular focus on AD.
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