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ABSTRACT Drosophila’s innate response to gravity, geotaxis, has been used to assess the impact of aging and disease on motor performance. Despite its rich history, fly geotaxis continues to be largely measured manually and assessed through simplistic metrics, limiting analytic insights into the behavior. Here, we have constructed a fully programmable apparatus and developed a multi-object tracking software capable of following sub-second movements of individual flies, thus allowing quantitative analysis of geotaxis. The apparatus monitors 10 fly cohorts simultaneously, with each cohort consisting of up to 7 flies. The software tracks single flies during the entire run with ∼97% accuracy, yielding detailed climbing curve, speed and movement direction with 1/30 s resolution. Our tracking permits the construction of multi-variable metrics and the detection of transitory movement phenotypes, such as slips and falls. The platform is therefore poised to advance Drosophila geotaxis assay into a comprehensive assessment of locomotor behavior. 

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 inDrosophilamodels 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.