Publication highlights

Aberrant protein-lipid interactions occur in neurodegeneration, although their role is unclear. We show how the protein α-synuclein interacts with lipids to drive a form of cell death, ferroptosis. As α-synuclein aggregates, oligomeric species with hydrophobic domains incorporate into the plasmalemmal membrane, leading to altered membrane conductance and abnormal calcium influx following glutamatergic and dopaminergic stimuli. Aggregates induce iron dependent generation of free radicals, and peroxidation of polyunsaturated fatty acids, which underlies the incorporation of aggregates into the membranes. Targeted inhibition of lipid peroxidation prevents the aggregate-membrane interaction, abolishes aberrant calcium fluxes, and restores physiological calcium signaling in human neurons, highlighting a new causative role for lipid homeostasis in Parkinson’s disease.

Through the use of aPKC inhibitors and genetic mutations, we demonstrate that aPKC cycles between distinct PAR-3 and CDC-42 dependent states, which define, respectively, the ability of the aPAR network to respond to spatial cues and to displace pPAR proteins from the membrane. We further show that cue sensing depends crucially on the oligomeric nature of the PAR-3 state, that the integrity of this cycle is required for coupling of cue-sensing and effector functions of the aPAR network, and that this cycle is enforced by activity of aPKC.

This paper is a continuation of our major research theme on how dividing stem cells in the CNS are able to resist environmental stresses that shut down proliferation in most other developing tissues. It reports the first identification, in any species, of lipid droplets as protectors of stem cells. We discovered that hypoxia induces lipid droplets in the neural stem cell niche and that these protect the neural stem cells themselves from damaging polyunsaturated fatty acid (PUFA) peroxidation reactions. This study laid the foundation for our current mechanistic studies into the antioxidant functions of lipid droplets during development and tumorigenesis.

The immune system is increasingly acknowledged to be integrated with general physiology, but the genetic pathways underpinning those are largely unknown. This study demonstrated that high-content immunophenotyping could be accomplished at scale, compatible with a genetic screen and in so doing identified 80 novel immunoregulators (“hits”) and established striking correlations of immunological traits with blood biochemistry markers such as cholesterol and sodium. The paper formed a basis for the successful and rapid application of high-content high-throughput profiling to COVID-IP and to cancer immunomonitoring, and has spawned mechanistic follow-up studies of several of the hits.

SARS-CoV-2 infection and life-threatening COVID-19 caused the world’s most severe infectious disease pandemic in 100 years. An immediate priority was to decipher what was happening to patients’ immune systems. Rapidly deploying its skill-sets in high-content, high-throughput immunoprofiling, the Immunosurveillance Laboratory identified a dynamic, COVID-19 immune signature that blended textbook immunoprotection with examples of immune dysregulation that today’s textbooks do not describe. Among those, three molecules measured upon hospital admission seemingly predict a patient’s likelihood of deterioration over the next week; knowledge which can benefit health-care resource management, and offer novel therapeutic targets in COVID-19 and other inflammatory infectious diseases.

This paper shows how temporal information in the zebrafish embryo is transformed into a spatial pattern. We demonstrate how the Nodal signalling gradient is formed in the early zebrafish embryo and show that its size and shape are determined by a temporal signal activation window created by a microRNA-mediated delay in the translation of Lefty, a Nodal antagonist. This paper was important as it not only challenged the long-held view in the field that the Nodal gradient was formed by a reaction–diffusion mechanism, but highlighted the importance of signalling duration in gradient formation.

How inflammatory programmes are tuned to recruit sufficient numbers of neutrophils to clear microbes of different size remained unknown. Furthermore, neutrophils were not thought to serve as major regulators of inflammation in vivo. We showed that reactive oxygen species localisation allows neutrophils to regulate their own recruitment by setting the appropriate level of cytokine production.