Modulation of sleep by trafficking of lipids through the Drosophila blood brain barrier

  1. Fu Li
  2. Gregory Artiushin
  3. Amita Sehgal  Is a corresponding author
  1. Howard Hughes Medical Institute, University of Pennsylvania, United States

Abstract

Endocytosis through Drosophila glia is a significant determinant of sleep amount and occurs preferentially during sleep in glia of the blood brain barrier (BBB). To identify metabolites whose trafficking is mediated by sleep-dependent endocytosis, we conducted metabolomic analysis of flies that have increased sleep due to a block in glial endocytosis. We report that acylcarnitines, fatty acids conjugated to carnitine to promote their transport, accumulate in heads of these animals. In parallel, to identify transporters and receptors whose loss contributes to the sleep phenotype caused by blocked endocytosis, we screened genes enriched in barrier glia for effects on sleep. We find that knockdown of lipid transporters LRP1&2 or of carnitine transporters ORCT1&2 increases sleep. In support of the idea that the block in endocytosis affects trafficking through specific transporters, knockdown of LRP or ORCT transporters also increases acylcarnitines in heads. We propose that lipid species, such as acylcarnitines, are trafficked through the BBB via sleep-dependent endocytosis, and their accumulation reflects an increased need for sleep.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1,2, 3, 4, 5, 6, 7, 8 and Figure1-supplement Figur1, Figure 2- figure supplement 1, Figure 3- figure supplement 1.3 ,4, 5 ,6, 7, 8. Figure 4- figure supplement 1, 2, 3, 4, 5, 6.

Article and author information

Author details

  1. Fu Li

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
  2. Gregory Artiushin

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1615-3012
  3. Amita Sehgal

    Chronobiology and Sleep Institute, Howard Hughes Medical Institute, University of Pennsylvania, Philadelphia, United States
    For correspondence
    amita@pennmedicine.upenn.edu
    Competing interests
    Amita Sehgal, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7354-9641

Funding

National Institute of Diabetes and Digestive and Kidney Diseases (R01DK120757)

  • Amita Sehgal

Howard Hughes Medical Institute

  • Amita Sehgal

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2023, Li et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,797
    views
  • 282
    downloads
  • 17
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Fu Li
  2. Gregory Artiushin
  3. Amita Sehgal
(2023)
Modulation of sleep by trafficking of lipids through the Drosophila blood brain barrier
eLife 12:e86336.
https://doi.org/10.7554/eLife.86336

Share this article

https://doi.org/10.7554/eLife.86336

Further reading

    1. Neuroscience
    Sara A Nolin, Mary E Faulkner ... Kristina Visscher
    Research Article

    The brain is organized into systems and networks of interacting components. The functional connections among these components give insight into the brain's organization and may underlie some cognitive effects of aging. Examining the relationship between individual differences in brain organization and cognitive function in older adults who have reached oldest old ages with healthy cognition can help us understand how these networks support healthy cognitive aging. We investigated functional network segregation in 146 cognitively healthy participants aged 85+ in the McKnight Brain Aging Registry. We found that the segregation of the association system and the individual networks within the association system [the fronto-parietal network (FPN), cingulo-opercular network (CON) and default mode network (DMN)], has strong associations with overall cognition and processing speed. We also provide a healthy oldest-old (85+) cortical parcellation that can be used in future work in this age group. This study shows that network segregation of the oldest-old brain is closely linked to cognitive performance. This work adds to the growing body of knowledge about differentiation in the aged brain by demonstrating that cognitive ability is associated with differentiated functional networks in very old individuals representing successful cognitive aging.

    1. Cell Biology
    2. Neuroscience
    Vibhavari Aysha Bansal, Jia Min Tan ... Toh Hean Ch'ng
    Research Article

    The emergence of Aβ pathology is one of the hallmarks of Alzheimer’s disease (AD), but the mechanisms and impact of Aβ in progression of the disease is unclear. The nuclear pore complex (NPC) is a multi-protein assembly in mammalian cells that regulates movement of macromolecules across the nuclear envelope; its function is shown to undergo age-dependent decline during normal aging and is also impaired in multiple neurodegenerative disorders. Yet not much is known about the impact of Aβ on NPC function in neurons. Here, we examined NPC and nucleoporin (NUP) distribution and nucleocytoplasmic transport using a mouse model of AD (AppNL-G-F/NL-G-F) that expresses Aβ in young animals. Our studies revealed that a time-dependent accumulation of intracellular Aβ corresponded with a reduction of NPCs and NUPs in the nuclear envelope which resulted in the degradation of the permeability barrier and inefficient segregation of nucleocytoplasmic proteins, and active transport. As a result of the NPC dysfunction App KI neurons become more vulnerable to inflammation-induced necroptosis – a programmed cell death pathway where the core components are activated via phosphorylation through nucleocytoplasmic shutting. Collectively, our data implicates Aβ in progressive impairment of nuclear pore function and further confirms that the protein complex is vulnerable to disruption in various neurodegenerative diseases and is a potential therapeutic target.