article published yes Chengji Piao author Ewelina Dutkiewicz author 0601cc46-c082-11ec-9b07-bb29641d1de9 Laxmikanth Kollipara author Albert Sickmann author Sheng Huang author Stephan J. Sigrist author Sleep need is associated with both circuit dynamics and widespread synaptic plasticity, yet the specific synaptic changes underlying sleep homeostasis remain incompletely understood. In Drosophila, sleep loss has been shown to trigger plasticity of the presynaptic active zone, marked by increasing levels of the ELKS-family scaffold protein Bruchpilot (BRP). By titrating brp gene copy number, we previously established a presynapse-specific, dosage-dependent paradigm that modulates sleep pressure. Here, to elucidate the molecular landscape of this plasticity, we performed synapse-enriched integrated-omics. Proteomic and bioinformatic analyses revealed changes in immune and stress response pathways and local translation control. Strikingly, phospho-proteomic analysis uncovered a global shift toward hypophosphorylation, particularly in presynaptic proteins, indicating a reprogramming of the phosphorylation–dephosphorylation balance. This presynaptic hypophosphorylation is likely contributed by reduced activity of Protein Kinase A (PKA) and enhanced substrate affinity of Protein Phosphatase 1 (PP1) mediated by its regulatory subunit Spinophilin (Spn). Manipulating either PKA or PP1 activity was sufficient to suppress BRP-modulated sleep phenotypes. We propose that presynaptic hypophosphorylation constitutes a molecular signature of local synaptic remodeling that adaptively tunes sleep need via reversible posttranslational modification, a mechanism likely conserved across species. https://research-explorer.ista.ac.at/download/22733/22737/2026_PNAS_Piao.pdf application/pdfno https://creativecommons.org/licenses/by/4.0/ National Academy of Sciences2026 eng 0027-8424 1091-6490 4225871310.1073/pnas.2524065123 12324 yes Piao C, Dutkiewicz E, Kollipara L, Sickmann A, Huang S, Sigrist SJ. Active zone plasticity couples sleep need to presynaptic hypophosphorylation. <i>Proceedings of the National Academy of Sciences</i>. 2026;123(24). doi:<a href="https://doi.org/10.1073/pnas.2524065123">10.1073/pnas.2524065123</a> Piao, Chengji, Ewelina Dutkiewicz, Laxmikanth Kollipara, Albert Sickmann, Sheng Huang, and Stephan J. Sigrist. “Active Zone Plasticity Couples Sleep Need to Presynaptic Hypophosphorylation.” <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences, 2026. <a href="https://doi.org/10.1073/pnas.2524065123">https://doi.org/10.1073/pnas.2524065123</a>. Piao, C., Dutkiewicz, E., Kollipara, L., Sickmann, A., Huang, S., &#38; Sigrist, S. J. (2026). Active zone plasticity couples sleep need to presynaptic hypophosphorylation. <i>Proceedings of the National Academy of Sciences</i>. National Academy of Sciences. <a href="https://doi.org/10.1073/pnas.2524065123">https://doi.org/10.1073/pnas.2524065123</a> C. Piao, E. Dutkiewicz, L. Kollipara, A. Sickmann, S. Huang, and S. J. Sigrist, “Active zone plasticity couples sleep need to presynaptic hypophosphorylation,” <i>Proceedings of the National Academy of Sciences</i>, vol. 123, no. 24. National Academy of Sciences, 2026. C. Piao, E. Dutkiewicz, L. Kollipara, A. Sickmann, S. Huang, S.J. Sigrist, Proceedings of the National Academy of Sciences 123 (2026). Piao, Chengji, et al. “Active Zone Plasticity Couples Sleep Need to Presynaptic Hypophosphorylation.” <i>Proceedings of the National Academy of Sciences</i>, vol. 123, no. 24, e2524065123, National Academy of Sciences, 2026, doi:<a href="https://doi.org/10.1073/pnas.2524065123">10.1073/pnas.2524065123</a>. Piao C, Dutkiewicz E, Kollipara L, Sickmann A, Huang S, Sigrist SJ. 2026. Active zone plasticity couples sleep need to presynaptic hypophosphorylation. Proceedings of the National Academy of Sciences. 123(24), e2524065123. 227332026-08-18T10:46:33Z2026-08-20T05:35:33Z