How do reactive astrocyte lipids contribute to neuron dysfunction?

As astrocytes shift into a reactive state, they experience substantial alterations in gene expression, protein levels, and most critically, their functions. Despite reactive astrocytes being described for over a century, the cellular mechanisms triggering various states of reactive astrocytes remain elusive. This lack of understanding poses a significant hurdle to neurodegenerative disease research, given that reactive astrocytes feature in all neurodevelopmental, degenerative, and psychiatric disorders in humans. We have identified numerous sub-states of reactive astrocytes and observed an unexpected change in astrocyte lipid levels, specifically a rise in neurotoxic saturated lipids that could have implications for several neurological disorders. Our aim is to decipher how these shifts in astrocyte lipid production and metabolism affect neuronal function and disease progression. Our ultimate goal is to develop novel astrocyte-targeted therapeutics, thereby restoring neuronal function and providing new treatments for neurodegenerative diseases. This research has the potential to redefine our understanding of astrocyte biology and open new avenues for treating a wide range of neurological disorders.

A native of Australia, Dr. Shane Liddelow earned his Bachelor of Science (Hons) and Biomedical Science degrees from the University of Melbourne. He completed his PhD under the guidance of Katarzyna Dziegielewska and Norman Saunders in Pharmacology at the University of Melbourne. During his postdoctoral fellowship in the lab of Ben Barres at Stanford University, Shane made significant contributions to the field of astrocyte biology. He discovered a subtype of reactive astrocytes that release a toxic factor that kills neurons. He showed that these neurotoxic reactive astrocytes are evolutionarily conserved from rodents to humans, and that they are present in the brains of patients with Alzheimer’s, Parkinson’s, Huntington’s disease, ALS, and several other diseases. More recently his lab identified the exact toxic molecule these astrocytes secrete – a long chain saturated lipid – and they are currently working to further understand how these lipids are generated and researching avenues to modulate their production in the context of disease. Since moving to NYU Grossman School of Medicine in 2018, his lab continues to uncover novel substates of reactive astrocytes – defining their function across disease. In 2021, he was appointed Co-Director of the Parekh Center for Interdisciplinary Neurology at NYU – a research center tasked with fostering collaboration and driving discovery of treatments for multiple neurological diseases. In 2024, he was promoted to Associate Professor. Shane has received many awards, including the Inge Grundke-Iqbal Award for Alzheimer’s Research (2019), the David Hague Early Career Investigator of the Year Award (Alzheimer’s Research UK, 2020), the Janett Rosenberg Trubatch Career Development Award (SfN, 2021) and the Harry Weaver Award from the National MS Society (2021). Since 2020, he has been listed as a highly cited researcher by Clarivate/Web of Science – which recognizes researchers in the top 1% of citations worldwide.

"The MIND Prize is enabling us to delve deeper into the complex world of astrocyte lipids and their role in neurodegeneration. We’re using cutting-edge synthetic genetic engineering technology to create mouse embryonic stem cells that lack key lipid production and breakdown enzymes. This will allow us to explore how toxic lipids are produced and how they affect neurons."

Our team will investigate the role of astrocytes in producing neurotoxic lipids. These lipids are implicated in the death of neurons in a number of different neurodegenerative diseases including Alzheimer's disease, glaucoma, among others.

"Our research is fundamentally changing the way we understand the role of glial cells, particularly astrocytes, in the central nervous system. We’re investigating how these cells interact with immune cells and neurons during health and disease. Our ultimate goal is to develop astrocyte-targeted therapeutics that can improve neuron function and provide new treatments for neurodegenerative diseases."