Tau is required for glial lipid droplet formation and resistance to neuronal oxidative stress
The accumulation of reactive oxygen species (ROS) is a common feature of tauopathies, defined by Tau accumulations in neurons and glia. High ROS in neurons causes lipid production and the export of toxic peroxidated lipids (LPOs). Glia uptake these LPOs and incorporate them into lipid droplets (LDs) for storage and catabolism. We found that overexpressing Tau in glia disrupts LDs in flies and rat neuron-astrocyte co-cultures, sensitizing the glia to toxic, neuronal LPOs. Using a new fly tau loss-of-function allele and RNA-mediated interference, we found that endogenous Tau is required for glial LD formation and protection against neuronal LPOs. Similarly, endogenous Tau is required in rat astrocytes and human oligodendrocyte-like cells for LD formation and the breakdown of LPOs. Behaviorally, flies lacking glial Tau have decreased lifespans and motor defects that are rescuable by administering the antioxidant N-acetylcysteine amide. Overall, this work provides insights into the important role that Tau has in glia to mitigate ROS in the brain.
Authors
- Oguz Kanca (ORCID: https://orcid.org/0000-0001-5438-0879)
- Ye-Jin Park (ORCID: https://orcid.org/0000-0002-8066-4194)
- Joshua M Shulman (ORCID: https://orcid.org/0000-0001-6382-5841)
- Pinghan Zhao
- Matthew J. Moulton (ORCID: https://orcid.org/0000-0003-0228-7669)
- Isha Ralhan (ORCID: https://orcid.org/0000-0002-6890-2620)
- Hugo J. Bellen (ORCID: https://orcid.org/0000-0001-5992-5989)
- Maria S. Ioannou (ORCID: https://orcid.org/0000-0001-6252-8626)
- Shenzhao Lu (ORCID: https://orcid.org/0000-0003-3117-3900)
- Lindsey D. Goodman (ORCID: https://orcid.org/0000-0002-9255-3811)
- Kai Sun (ORCID: https://orcid.org/0000-0002-4778-4549)
- Julie Jacquemyn (ORCID: https://orcid.org/0000-0002-4524-5728)
- Kanae Ando (ORCID: https://orcid.org/0000-0002-3956-276X)
- Ziyaneh S. Ghaderpour Taleghani (ORCID: https://orcid.org/0000-0001-9399-6502)
- Xin Li
Institutions
- University of Alberta (CA)
- Baylor College of Medicine (US)
- Neurological Research Institute (US)
- Women and Children’s Health Research Institute (CA)
- Brown Foundation (US)
- Texas Children's Hospital (US)
- Baylor Genetics (US)
- Tokyo Metropolitan University (JP)
- The University of Texas Health Science Center at Houston (US)
Publication Details
- Journal
- Nature Neuroscience
- Published
- 2024-08-26
- DOI
- https://doi.org/10.1038/s41593-024-01740-1
- Citations
- 40
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 11.80
Funders
- Alfred P. Sloan Foundation
- BrightFocus Foundation
- Rush University
- Translational Genomics Research Institute
- University of Alberta
- Canada Research Chairs
- National Institutes of Health
- Canadian Institutes of Health Research
- Japan Society for the Promotion of Science
- National Institute on Aging
- National Institute of General Medical Sciences
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Neurological Disorders and Stroke
- National Institute of Child Health and Human Development
- Common Fund