Thanks in large part to the seminal work of Steve White and his colleagues, we appreciate the "ordered complexity" of the lipid bilayer and how it impacts the incorporation of integral membrane proteins as well as more peripherally associated proteins. Steve's work also provides a vital foundation to tackle another challenge: cytotoxic oligomeric complexes which accumulate in various neurodegenerative diseases. These oligomers have a relatively fluid structure and interact with many different proteins in the cell, but their main target is thought to be the phospholipid membrane, either the plasma membrane or internal organelles such as the mitochondria. This fascinating encounter between two essentially fluid phases generates a more disordered membrane, and presumably promotes uncontrolled transport of small metal ions across the membrane barrier. Happily, this unwanted interaction may be suppressed by mobilizing the phospholipid bilayer into its own defense. Extruded nanolipoparticles (NLPs) consisting of DPPC lipids, cholesterol and PEG2000 are excellent vehicles to take up small "oligomer-bashing" hydrophobic molecules such as baicalein and transport them with increased half-life in the plasma and with markedly more efficient crossing of the blood-brain barrier. Thus the bilayer has a triple role in this account: a safe space for a reactive hydrophobic small molecule, a barrier to cross to deliver a drug payload and a target to protect against oligomer attacks. NLPs containing small hydrophobic molecules show great promise in combating neurodegenerative diseases in animal models and may serve as an example of the White approach: applying robust physical-chemical principles to deal with biological problems involving phospholipid membranes.
Keywords: Alpha-synuclein; Neurodegenerative diseases; Toxic oligomers.