Elucidating the pathological mechanisms of neurodegeneration in the lethal serpinopathy FENIB

The term serpinopathies was introduced to describe a family of diseases caused by point mutations in serine protease inhibitors, or serpins. Serpins inhibit their cognate protease by an irreversible suicide mechanism starting with the attack of the active site serine on the reactive center loop of the inhibitor, followed by formation of a covalent complex between both proteins, insertion of the reactive center loop of the serpin into its own beta-sheet A, and culminating in distortion of the active site of the serine protease and thus irreversible inactivation. This inhibitory mechanism, reminiscent of the movement of a mousetrap, requires a structural flexibility that proves to be unfavorable when the folding of the serpin is altered by mutations responsible for conformational rearrangements, allowing an intermolecular domain exchange characterized by the insertion of the C-terminal domain of a molecule into a second one, thus forming a dimer. Expansion of this insertion reaction leads to the formation of serpin polymers that accumulate within the endoplasmic reticulum (ER) of the cell and consequently reduces the secretion of the wild-type serpin (Greene et al., 2016).