From molecules and cells to mice and men: investigating the role of kinases in psychiatric and neurological disorders

Eleanor Coffey is a researcher with a special focus in mind. She works on kinases, a diverse set of proteins that function to switch other proteins and consequently molecular signaling pathways on or off. Altogether ten researchers work in her lab including Master’s students. The group’s work is currently divided into two roughly equal parts. One area focuses on the role of a kinase called JNK in psychiatric disorders. In that project they have recently found that JNK plays an important role in anxiety and depressive-like behavior in mice. The second project is about a kinase called LRRK2 in Parkinson’s disease. The group noticed that LRRK2 appears to repress protein synthesis in Parkinson’s disease models and in patient skin cells. As there is no biomarker for Parkinson’s disease, they created a project called PARKS to develop a Parkinson’s Disease diagnostic test with the aim of going into the clinic and producing a commecial kit. Eleanor’s group is working in collaboration with movement disorder specialist, Professor Valtteri Kaasinen at TYKS hospital and the Parkinson’s Progression Markers Initiative (PPMI), an international cohort supported by the Michael J. Fox Foundation. The group has submitted a family of patents for evaluation related to biomarkers for Parkinson’s. This is a good example of how innovations can be initiated by a collaboration between basic and clinical researchers.

White blood cells are the most important building block in their research in trying to understand the mechanims behind the diseases from a biological and clinical standpoint. Eleanor’s group uses blood samples from clinical cohorts from which they isolate mononuclar white blood cells. As Eleanor herself descibes: “We are very focused on cells right now, because we are intested not only in identifying markers which will predict disease but we are also trying to understand the disease mechanisms using omic technologies. When you look at plasma, you only see what is secreted by the cells. When you look inside the cells themselves, you gain more insight on the underlieing mechanism.” The group is focused on investigating the pathways associated with the two diseases. As humans all have about 42 million protein copies in each cell, it means that without deep coverage methods, it would be impossible to analyze the data. With new mass spectrometry instruments it is possible to identify and quantitate a very large percentage of these proteins. The group has set up an automated clinical proteomics platform in order to follow the effects of LRRK2 kinase in these blood cells. This platform is now being used to study a treatment resistant depression cohort as part of a clinical trial in Germany, where the goal is to find a biomarker in patient blood that can predict in advance if they will have a respond to treatment with the antidepressive drug Ketamine or not.

However, the group goes in deeper still, using techniques ranging from single cell analysis of cells to looking into brain circuitry using flourescent microscopy techniques using live animals and correlating with the behavioral in the individual animals. By injecting viruses to periphery it is possible to modify genes in the mouse brain and inhibit certain kinases. Using fibre photometry it is possible to measure the neuronal activity of individual mice during specific behavioural patterns. This, combined with optogenetics tools helps in identifying which circuits are driven by certain kinases. As Eleanor describes, it is possible to inhibit the kinases very selectively: “It is sufficient to inhibit the kinase in just 200 cells in a particular part of the hippocampus and the behavior of the mice changes.” The lab uses the same tools that are under developent for gene therapy for CNS disorders to explore how JNK drives behavior from specific cell types.

The group indeed has lots going on and as the cherry on the cake, the group also got a funding from Academy of Finland for research into long term mental disorders caused by side effects of COVID-19 infection. Currently the samples come from Germany and US, but the group is also searching for samples from Finland.

In addition to the kinase research, Eleanor is also the head of the Cell Imaging and Cytometry (CIC) centre and the Genome Editing facility which provides instrumentation and technical support for researchers and industry customers to carry out imaging techniques. CIC is part of Biocenter Finland Biological imaging network. For more information about the services of CIC, please visit following web page: https://bioscience.fi/services/cell-imaging/services/. Currently companies in Finland use the centres, and they are planning to offers these service abroad also.

In case of questions or collaboration requests, you can contact Eleanor’s group:
eleanor.coffey@bioscience.fi