Øyvind Halskau

Lipids as catalysts of protein misfolding

For a fairly recent invited lecture, please see this youtube video.

The unit of life is the cell. Its outer border is the cell membrane, a thin sheet just a few nanometers thick. This is not a solid barrier, but rather a semi-fluid oil-like affair. It consists of lipids, molecules similar to fats or oils and proteins. There are also chains of sugar molecules linked to it. The cell membrane allows some molecules to pass through it, but is impassable to others. Many of both the protein, lipid and sugar molecules of the cell membrane are well-understood in terms individual behavior. But in the complex and constantly changing environment of the membrane it has remained a challenge to understand how each component may affect each other. And understanding this interplay is critical for understanding the molecular foundation of the cell. This project intends to examine how lipids affect proteins and how proteins affect the integrity of the lipid assembly that gives the cell membrane its integrity as a barrier. One of the main questions asked is whether some lipids or states of the membrane can cause certain proteins to misform. Proteins normally need to twist their shape into a specific structure, or fold, to gain their function. If this process, which is usually spontaneous, is disturbed, they can form damaging states instead. This is normally referred to as protein misfolding, and we asks whether some lipids can prompt certain membrane-associated proteins to misfold at a quicker pace than they normally would. Such misfolding events are implicated in many diseases, including Parkinson's, Alzheimer's and Diabetes II, as well as prionic diseases. If the scientific question is well posed and the project manages to pursue it with appropriate techniques it is possible that one might gain new and detailed insight into disease mechanisms. This could in time lead to better prevention or treatments. Our preliminary findings indicate that cells modulate their lipid composition to a large extent throughout their life-time. The lipid mixes are so different that that the physical properties of the membrane changes significantly. We also find that different lipid mixes affect the aggregation-rates of model peptide systems.

We aim to use zebrafish as model organism to conduct neurolipidomics related to ageing and (models) of neurodegenerative diseases. Using biophysics and structural biology, we will investigate whether certain lipids and membrane associated proteins, in particular phosphoinositides and so-called scaffold proteins , act as moderators of misfolding. The biophysics and structural biology of this is being investigated, with a focus on “invisible protein states”, i.e., states that are not detectable by normal means. We also wish to know where in a cell misfolded protein accumulates, and whether this localization can be linked to lipid metabolism, thereby establishing a link between misfolding and lipidome. We will introduce of misfolders (in functional, misfolded and inert states) into cells to discover subcellular locations affected by misfolding, with a particular attention to functional assemblies of lipases, cholesterol and phosphoinesotides.

I also work with the structural biology and biophysics of Chromatine Regulation, as well as the structural biology of honey bees in collaboration with Gro Amdam.