Zenon Toprakcioglu C@C taken by Michael Webb ©University of Cambridge
Dr Zenon Toprakcioglu studies protein misfolding diseases in the Knowles group. His latest research studies how lipids found naturally in our cells and in the brain’s grey matter could slow down the formation of protein aggregates.
Fats and proteins
Clumps of the aggregated protein amyloid-beta (Aβ) have long been associated with Alzheimer’s disease. These aggregates, also known as amyloid fibrils or amyloid plaques, accumulate in the brain over time and eventually lead to neuron death.
We don’t know why these aggregates form, but one hypothesis is that lipids and lipid membranes can affect their formation. In fact, increasing evidence suggests that lipid membranes play a critical role in regulating protein function. This means that malfunctions in lipid composition could have a direct effect on proteins and possibly result in the promotion of toxic protein states.
Gangliosides
Gangliosides are a type of lipid, or fat, which are abundant in the brain and are essential for cell communication and signalling. They have also been associated with neuro-protection and neuro-restoration. Ganglioside lipids are mainly found in the outer layer of the cell membrane, which is the part that is in contact with the extracellular environment and with the amyloid-beta protein.
Because of their location and the fact that the number of ganglioside lipids decreases with age, we wanted to investigate the role (if any) they have on the aggregation of amyloid-beta toxic protein states.
Our project
For this project, we used complex kinetic experiments and theory to investigate the interaction between ganglioside lipids and the two most abundant forms of amyloid-beta (Aβ42 and Aβ40). We discovered that ganglioside lipids have the ability to completely inhibit the aggregation of Aβ40 and partially inhibit the aggregation of Aβ42. Through our experiments, we were able to show that gangliosides can form complexes with the proteins which disrupt the aggregation pathway and result in delayed aggregation.
Future work
We believe that through further in-depth experimentation, we can achieve a fundamental understanding of what happens during interactions between proteins and lipids in neurodegenerative disease. My aspiration is that this line of investigation will pave the way for the identification of new molecular targets involving lipids, which could lay the foundation for new therapies in the fight against neurodegenerative disorders. In the long-term, this will hopefully improve the lives of people suffering from these ailments.
This article first appeared in Chem@Cam magazine Spring 2024 Issue 68 pg 22.