RT Journal Article SR Electronic T1 Regulation of proteostasis by sleep through autophagy in Drosophila models of Alzheimer’s disease JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e202402681 DO 10.26508/lsa.202402681 VO 7 IS 11 A1 Ortiz-Vega, Natalie A1 Lobato, Amanda G A1 Canic, Tijana A1 Zhu, Yi A1 Lazopulo, Stanislav A1 Syed, Sheyum A1 Zhai, R Grace YR 2024 UL http://www.life-science-alliance.org/content/7/11/e202402681.abstract AB Sleep and circadian rhythm dysfunctions are common clinical features of Alzheimer’s disease (AD). Increasing evidence suggests that in addition to being a symptom, sleep disturbances can also drive the progression of neurodegeneration. Protein aggregation is a pathological hallmark of AD; however, the molecular pathways behind how sleep affects protein homeostasis remain elusive. Here we demonstrate that sleep modulation influences proteostasis and the progression of neurodegeneration in Drosophila models of tauopathy. We show that sleep deprivation enhanced Tau aggregational toxicity resulting in exacerbated synaptic degeneration. In contrast, sleep induction using gaboxadol led to reduced toxic Tau accumulation in neurons as a result of modulated autophagic flux and enhanced clearance of ubiquitinated Tau, suggesting altered protein processing and clearance that resulted in improved synaptic integrity and function. These findings highlight the complex relationship between sleep and regulation of protein homeostasis and the neuroprotective potential of sleep-enhancing therapeutics to slow the progression or delay the onset of neurodegeneration.All data are available in the main text or the supplementary materials.