Publication highlights

Researchers at the Crick and UCL have shown that reported that astrocytes show signs of hypoxic stress long before neurons begin to die in ALS. Using stem cells from patients to generate astrocytes carrying ALS-linked mutations in a gene called VCP, which is linked to inherited forms of ALS, the team showed that astrocytes exhibited clear signs of 'pseudo-hypoxia'. This meant they had switched on a low-oxygen response despite being in normal oxygen conditions. This was driven by HIF-1a, a master regulator of how cells respond to oxygen. Instead of being degraded under normal conditions, it had accumulated in the nucleus and activated genes involved in metabolism, energy production and stress responses. As a result ALS astrocytes showed mitochondrial dysfunction and a reduced ability to support motor neurons. This is particularly exhibited as an inability to correct the mislocalisation of RNA-binding proteins, a well-known molecular hallmark of ALS, compromising neuron survival.

A team of scientists from the University of Cambridge, the Crick and the Polytechnique Montreal have, for the first time, directly visualised and quantified the protein clusters believed to trigger Parkinson's disease. Their new technique uses ultra-sensitive fluorescence microscopy to detect and analyse millions of oligomers in post-mortem brain tissue. They found that oligomers exist in both healthy brains and brains from people with Parkinson's disease, but the main difference was the size of the oligomers, which were larger, brighter and more numerous in disease samples, suggesting a direct link to the progression of the disease. They also observed a sub-class of oligomers that appeared only in people with Parkinson's disease, which could be the earliest viable markers of the condition, appearing potentially years before symptoms appear.

Researchers at the Crick and UCL have shown that genetic messages, called mRNAs, are misplaced in nerve cells in a model of Alzheimer's disease and frontotemporal dementia. They looked at corticial neurons specialised from skin cells from people with inherited forms of Alzheimer's disease or FTD who had mutations in APP or PSEN1 genes (Alzheimer's disease) and VCP (FTD). Between 82 and 140 mRNAs were found in a different place in the neurons with the mutations compared to control neurons. These included ten that were common to both diseases, all found to carry messages from genes related to mitochondrial function. The team also found that mitochondrial DNA was leaking out of the mitochondria, and that diseased neurons had fewer and smaller mitochondria. Treating these cells with a drug called ML240 returned the misplaced mRNAs to their typical locations, reduced the amount of mitochondrial DNA leakage and raised mitochondrial activity back to normal levels.

Researchers at UCL and the Francis Crick Institute have, for the first time, identified the origin of cardiac cells using 3D images of a heart forming in real-time, inside a living mouse embryo. The team used a technique called advanced light-sheet microscopy on a specially engineered mouse model, where a thin sheet of light is used to illuminate and take detailed pictures of tiny samples, creating clear 3D images without causing any damage to living tissue. They were able to track individual cells as they moved and divided over the course of two days – from a critical stage of development known as gastrulation through to the point where the primitive heart begins to take shape. This allowed the researchers to identify the cellular origins of the heart. The study’s findings could revolutionise how scientists understand and treat congenital heart defects.

Researchers at the Crick and UCL Queen Square Institute of Neurology have shown that alpha-synuclein, the protein that aggregates in Parkinson’s disease, can trigger widespread RNA editing in astrocytes as part of an anti-viral innate immune response. They used human stem cells to generate astrocytes, the most abundant cell type in the brain. Using molecular biology, genomic and computational approaches, they showed that forms of alpha-synuclein trigger the same innate immune pathways in astrocytes that viruses do. One consequence of this response was a marked increase in RNA editing, with extensive changes throughout the genetic code as it is converted into proteins.

Previous work has found that, surprisingly, olfaction is a high-frequency sense: mice can discriminate odour fluctuations at 40 Hz or more. What could this high-frequency acuity be used for? By analyzing simulations of two-dimensional air flow containing multiple odour sources, researchers at the Crick show that high-frequency odour fluctuations contain more information about how far apart two odour sources are than low frequencies. This suggests that the high-frequency acuity helps mice build accurate olfactory maps of their environments, a sort of passive SONAR, but using smells instead of sound.

Tuberculosis is most commonly thought of an encountered as a lung disease. However it may also enter the brain to cause meningitis (TBM) which causes death or disability in approximately 50% of those affected and kills approximately 78200 adults every year. Antibiotic treatment is based on that used for lung disease which overlooks important differences in the ability of drugs to reach the brain. TBM has a profound inflammatory component which also requires treatment, yet only steroid have shown benefit. There is now an active pipeline of new anti-TB drugs, and the increasing availability of better and more specific anti-inflammatory therapies could bring a a new era of improved TBM treatment and outcomes. Yet, to date, TBM studies have been relatively few, progress is slow, and a new approach is required. In this article the views of a global consortium of TBM researchers are articulated towards a coordinated, definitive way ahead via globally conducted clinical trials of novel drugs and regimens to advance treatment and improve outcomes from this life-threatening infection.

The Stem Cell Biology and Developmental Genetics Laboratory at the Crick has shown that in a mouse model of human hypopituitarism, low doses of aspirin and the balance of bacteria in the gut can influence symptoms. The brains of these mice, which lack the Sox3 gene, had a reduced number of a hypothalamic cell type, NG2 glial cells. Treating Sox3-deficient animals with a low dose of aspirin for 21 days increased NG2 glia numbers and reversed the hypopituitarism, but highly surprisingly, the makeup of the gut microbiome also had a significant effect; the change in microbiome resulting from the mice migrating into the Crick animal facility from elsewhere was enough to rescue the hormonal deficiencies. In addition to providing a clear case where extrinsic factors can influence a robust phenotype caused by a mutation, the work has implications for experimental consistency between research facilities, and has garnered wide interest in the field.

How can cellular signalling quickly change the set of expressed genes (transcriptome) to drive fast biological changes? The RNA Networks Laboratory used deep learning to discover dynamic RNA binding patterns, or ‘mRNA hubs’, at the ends of mRNAs that control a developmental cell fate transition. These mRNA hubs undergo major changes in ribonucleoprotein assembly upon ERK signalling. This signalling leads to phosphorylation of the protein LIN28A, which then converges within mRNA hubs with another protein, PABP, to induce selective decay of mRNAs which are no longer needed to maintain pluripotent cell fate. This is required for progression of early development.