Nature Structural Biology pp 312 - 321

Alzheimer's disease is not the only disease that involves the abnormal deposition of proteins, forming structures known as amyloid (meaning starch-like) plaques. However, we rarely hear about numerous other diseases that involve amyloid plaques, such as the rare disease called familial amyloid polyneuropathy (FAP).

FAP is caused by the irregular build-up of the protein transthyretin into needle-like structures called fibrils, which become deposited throughout nerve and muscle tissues, disrupting their functions. In many cases, nerves and vessels in the extremities are first affected, with symptoms including numbness, lack of feeling in the toes and fingers, burning sensations, leg weakness, and bruising of the face as the result of protein deposition around fragile blood vessels. Later, the nerves that affect the gastrointestinal tract and blood pressure regulation may be affected, and heart problems may occur. FAP can result in death within 10 years of diagnosis.

The transthyretin protein normally functions as a complex (called a tetramer) of four identical monomeric units. Only the individual monomers can associate to form fibrils; the tetramers cannot. Inherited mutations that can lead to FAP cause the tetramers to dissociate into monomers more often, thus increasing the tendency to form fibrils. It has been proposed that a drug that could interact with and stabilize the transthyretin tetramer in patients might aid in the treatment of FAP.

Now, James Sacchettini, of Texas A&M University, and colleagues have rationally designed certain compounds that may prove useful as potential drugs to treat FAP, or as lead compounds for developing other, more useful compounds. Their designs were based on the atomic resolution structure of the transthyretin tetramer. The compounds they designed interacted as expected with transthyretin (based on the structures of transthyretin in complex with each drug), and also stabilized the tetramer and inhibited transthyretin fibril formation in the test tube.

The Editorial discusses FAP and other amyloid diseases.