Lindberg, Iris

The prohormone convertases PC1/3 and PC2 are eukaryotic serine proteases involved in proteolytic maturation of peptide hormone precursors and implicated in a variety of pathological conditions, including obesity, diabetes, and neurodegenerative diseases. In this work, we screened 45 compounds obtained by derivatization of a 2,5‐dideoxystreptamine scaffold. We found four promising PC1/3 competitive inhibitors and three PC2 inhibitors exhibiting various inhibition mechanisms with sub‐ and low micromolar inhibitory potency against a fluorogenic substrate. Low micromolar concentrations of certain compounds blocked the processing of the physiological substrate proglucagon. Interestingly, we identified compounds that were able to stimulate both 87 kDa PC1/3 and PC2 activity. Molecular modeling studies revealed interactions of the PC1/3 inhibitors with the active site that suggest structural modifications to further enhance potency. In support of experimental data suggesting that PC2 inhibition likely occurs via an allosteric mechanism, we identified several possible allosteric binding sites using computational searches. This work was supported by DA050854 to Iris Lindberg.

Significance Aberrant protein homeostasis (proteostasis) is increasingly recognized as a major causal factor in the development of protein aggregates, including aggregation of α-synuclein in Parkinson’s disease. Cellular proteins known as chaperones control proteostatic processes and are strongly associated with many different neurodegenerative diseases. We show here that an abundant brain- and endocrine-specific secretory chaperone known as proSAAS (named after four residues in the amino terminal region) exhibits potent antiaggregant effects on α-synuclein aggregation, and we identify a region of the protein that is necessary for this antiaggregant effect. We further show that proSAAS expression is able to stop α-synuclein from killing dopaminergic cells in a nigral cell model of Parkinson’s disease. This work demonstrates an important role for the proSAAS protein in blocking aggregation in neurodegeneration.