Hypersensitive mousetraps, a,-antitrypsin deficiency and dementia

a,-Antitrypsin functions as a 'mousetrap ' to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant ( G ~ u ~ ~ ' + Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and p-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of cir-culating protein predisposes the Z a,-antitrypsin homozygote to emphysema. Loop-sheet poly-merization is now recognized to underlie deficiency variants of other members of the ser-ine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and a,-anti-chymotrypsin, which are associated with throm-bosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin in-clusion bodies. Our understanding of the struc-tural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must Key words: inclusion bodies, loop-sheet polymerization, mutations, neutrophil elastase, serpins. 'To whom correspondence should be addressed (e-mail da