If you are looking to gain a better understanding of neurodegenerative disorders such as Alzheimer’s and Parkinson’s, it makes good sense to study protein-driven lipid transport in the body’s cells.
And that is exactly what Assistant Professor Joseph Lyons from the Department of Molecular Biology and Genetics at Aarhus University will be spending the next five years of his working life doing.
Joseph Lyons is one of the nine talented researchers who will become a Lundbeck Foundation Fellow in 2020, and the grant accompanying his appointment will enable him to establish his own research group at Aarhus University.
‘I will look at protein-driven lipid transport in relation to Alzheimer’s and Parkinson’s diseases,’ says Joseph Lyons.
There are some very complex transports of lipids that take place internally in all cells of the body across the cell membrane. This protein-driven transport is popularly known as the ‘lipid-flip-flop process’, as it is controlled by two groups of proteins – lipid flippases and floppases.
Joseph Lyons explains that by regulating the composition of lipids in the cells, for example, the process is also involved in a variety of basic biological processes in humans and other mammals; for instance, signalling systems that control blood coagulation and processes in relation to the cell’s life cycle.
In addition, dysfunction of these two protein groups in different ways, which we do not yet understand in detail, also plays a role in various diseases in humans, including neurodegenerative disorders and cancer.
Joseph Lyons has been studying the ‘flip-flop process’ for a number of years – since 2013, at Aarhus University under Professor Poul Nissen of DANDRITE (The Danish Research Institute of Translational Neuroscience). And in the summer of 2019, in collaboration with colleagues from Aarhus University and from German and French universities, Joseph Lyons was able to show the first ever 3D images of flippases. These results were published in a scientific article in Nature.
Flippases and other proteins are too small for traditional photographs to be taken of them. However, using cryo-electron microscopy – a technique where the proteins are examined at temperatures as low as -170oC – a 3D model can be created of both flippases and floppases. And now you can begin to understand how they work – and how dysfunction in the ‘flip-flop process’ can take place in different disease states.
‘The very first cryo-electron microscopy studies that we’ll be carrying out in my group will be about gaining more knowledge about how flippases and floppases are regulated down to the atomic level,’ says Joseph Lyons. The next phase of the project involves experiments at the cellular level. Here Joseph and his colleagues will study the transport of lipids in genetically engineered cells – both in healthy and in dysfunctional cells.
Joseph Lyons says that, in the longer term, knowledge from these studies should make it possible to investigate a hypothesis that links to Alzheimer’s and Parkinson’s diseases: ‘In particular, that dysfunction in the ‘flip-flop process’ may be involved in the accumulation of misfolded proteins – plaques – characteristic of these two neurodegenerative disorders.’