Tau spreading coordinates intercellular lipid flux enhancing neuronal resilience to lipid toxicity
The presence of intrinsically disordered proteins (IDPs) in the extracellular environment of the brain suggests that protein disorder may serve functions beyond those confined to the intracellular space. Tau, a prototypical IDP linked to tauopathies, a class of neurodegenerative diseases, is continuously released and spreads between cells in the brain, yet the biological significance of this…
Recent research reveals that tau, a protein implicated in neurodegenerative diseases, plays a crucial role in regulating lipid homeostasis within the brain. As an intrinsically disordered protein (IDP), tau releases and spreads between brain cells, although its extracellular function has been unclear. This study demonstrates that spreading tau enhances neuronal resilience to lipid toxicity by coordinating neutral lipid homeostasis.
By analyzing genetic and lipid data, researchers found that tau spreading reprograms lipid transport pathways and redistributes triacylglycerol pools, fundamentally altering neutral lipid metabolism. Upon cellular uptake of tau, it accumulates in neutral lipid-rich compartments, leading to increased neuronal lipid efflux. The exported lipids are enriched with peroxidized species, which are subsequently transferred to astrocytes.
This transfer helps reduce neuronal lipid stress, showcasing a mechanism through which tau regulates lipid homeostasis.
The findings suggest that tau's extracellular phase is an active mediator of cell-to-cell communication, coordinating tissue metabolism. Disruption of this homeostatic function may contribute to the metabolic dysfunction observed in the early stages of tauopathies. Thus, tau's role in intercellular lipid flux expands the understanding of protein disorder's involvement in cell signaling.
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