Our body consists of ~1013 cells: blood cells, liver cells, skin cells, etc etc. Almost all work done in our cells is performed by proteins and we have more than 20,000 different ones. A cell is not unlike a factory: there is energy supply and usage, waste collection and removal, and logistics to regulate transport into and out of the factory, as well as between rooms in the factory; we have hallways and walls, we have managers and regulators. From walls to managers to laborers and everything in between, proteins are all of this. They are like small machines that only function when they have been properly assembled. A small kink in the structure can have large consequences: halt of one of the protein machines, halt of the factory, disease, death. Almost all inherited diseases start with a defect in one of the proteins. And in age-related diseases, defective proteins accumulate and cause trouble.
To have hope for a cure for any disease, the therapeutic target needs to be identified. Drug-development efforts up to now focus on disease-specific targets: diet in metabolic diseases, cholesterol-lowering drugs in inherited hypercholesterolemia, gene therapy or gene editing for inherited diseases. Our consortium aims to find and characterize the therapeutic target at the basis: the faulty protein. Because all proteins lend their 3-D shape to only three major forces (hydrophobic interactions, hydrogen bonds, and charges), it is these 3 forces that make the difference between a functional, healthy protein and a protein that leads to disease. The ground-breaking idea of our proposal is that the full range of inherited and neurodegenerative diseases are caused by the same thing: a protein that does not attain its correct, functional shape. Although the same three forces are at work, the healthy interactions are replaced by disease-causing ones.