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Brain organoids model for studies of pathological crosstalk between astrocytes and microglia in Parkinson’s disease

Docent, University Researcher Šá���첹 Lehtonen from the A.I. Virtanen Institute for Molecular Sciences was granted a funding of 498,000 euros to study the cellular and molecular mechanisms that drive the development and progression of Parkinson’s disease (PD). The research can contribute to the development of new treatments and earlier diagnostics of the disease.

PD is the most common neurodegenerative movement disorder that affects more than 6 million people worldwide, and about 15,000 people in Finland. The motor symptoms are often preceded by non-motor symptoms and diagnosis is often made far too late when over 60% of dopaminergic neurons located in substantia nigra have already died. Despite decades of research, exact disease mechanisms are still unknown, and thus current treatments primarily rely on relieving symptoms.

In the project funded by Jane and Aatos Erkko Foundation, Lehtonen’s research group will focus on revealing the role of “non-cell-autonomous” mechanisms that involves the interaction of dopaminergic neurons with neighbouring glial cells such as astrocytes and microglia. The role of these glial cells in the pathogenesis of Parkinson’s disease is still poorly known, but there is growing evidence showing the contribution of these cells to non-cell-autonomous mechanisms in which neurodegeneration is strongly influenced by the toxicity of disease-specific proteins expressed in the glia. The researchers use pluripotent stem cell (iPSC) technology which allows the production of different brain cell types from patients’ fibroblasts. The interactions between different brain cell types are studied in several models, including 3D multicellular model and midbrain organoids.

“We have recently found out that astrocytes from PD patients produced significantly higher levels of α-synuclein, a protein that typically accumulates in dopaminergic neurons of PD patients’ brains, causing cell death. The PD patient astrocytes were also highly responsive to pro-inflammatory stimuli and more sensitive to inflammatory reactivation than control astrocytes,, says Lehtonen.

Lehtonen’s group will assess the role of microglia on astrocytic function and the consequence of glial interaction on dopaminergic neurons. 

“Our study will provide new and more accurate information about how these two integral central nervous system glial cells contribute to PD pathogenesis and allow us to identify key therapeutic targets and pathways responsible for pathological glial phenotype in PD.”

Novel antibiotics can be effective against antibiotic-resistant bacteria

Professor Antti Poso at the School of Pharmacy has secured 291,000 euros of funding for a project seeking novel approaches for the treatment of infections caused by antibiotic-resistant bacteria. The antibiotic, to be developed in international collaboration, is based on the inhibition of the SurA protein, which plays an essential role in the formation of the bacterial cell wall.

Antibiotic resistance is a global problem. More and more bacteria are resistant to antibiotics, and there is an urgent need to find new antibiotics to replace traditional ones. Funded by Jane and Aatos Erkko Foundation, the new antibiotic to be developed in the project will target the SurA protein. The key role of this protein in the formation of the cell wall of many gram-negative bacteria has been discovered only recently. “When the function of SurA is inhibited, the bacterial cell wall becomes weaker, allowing the body’s own defence mechanisms to destroy the bacterium. Combined with the SurA inhibitor, this also improves the efficacy of traditional antibiotics,” Professor Poso says, describing the project’s findings so far.

The approach is novel in that the primary aim of the new antibiotic is not to kill the bacterium, but to make it weaker. “When the drug doesn’t pose an immediate threat to the existence of the bacterium, it may be less inclined to develop resistance to it.”

The project will be carried out in collaboration with the University of Tübingen, the University of Antwerp, and the Max Planck Institute. Professor Poso’s research group in Kuopio is responsible for computer-assisted molecule design, as well as for the manufacturing of certain molecules, which will be tested in laboratory conditions. The project has already successfully developed the first promising SurA inhibitors, which will proceed to further studies.  The interaction between the SurA protein and the molecules that inhibit its function haven been simulated using the new Mahti supercomputer at CSC - IT Centre for Science.

For further information, please contact:

Šá���첹 Lehtonen, Docent, 91����, A.I. Virtanen Institute for Molecular Sciences

Professor Antti Poso, 91����, School of Pharmacy