|Titel:||Using small chemical compounds to inhibit polymerization of neuroserpin in FENIB||Sprache:||Englisch||Autor*in:||Ingwersen, Thies Frieder||Schlagwörter:||Neuroserpin; FENIB; Familiar Enzephalopathy with neuroserpin inclusion body; serpinopathy; neurodegeneration||Erscheinungsdatum:||2020||Tag der mündlichen Prüfung:||2021-01-11||Zusammenfassung:||
FENIB is an autosomal dominantly inherited neurodegenerative disease that leads to early onset dementia and epilepsy. It is caused by point mutations in NS, a serine protease inhibitor (serpin) predominantly expressed in the nervous system. These mutations lead to polymerization and accumulation of pathological mutants in cortical inclusion bodies. Polymer formation is caused by sequential insertion of the reactive center loop of one NS mutant into the β-sheet A of another. Using molecular dynamics simulations, small chemical compounds with high binding affinities to β-sheet A were identified as potential candidates to block loop-sheet-insertion. Here, we developed a screening assay to test 36 of these pre-selected compounds utilizing recombinantly produced NS. Additional to this in vitro characterization, 20 compounds were further tested in a cell culture model of FENIB.
We found that one compound (BUR) successfully reduced polymer formation in the in vitro assay. However, already formed polymers were not dissolved. Further research is needed to show if structural alterations to compound BUR enhance the anti-polymerizing effect. Another compound (G) significantly reduced the amount of NS polymers secreted by cells. However, intracellularly, increased amounts of polymerized NS were measured. Additionally, compound G showed no effect on recombinant NS in the in vitro experiments. Rather than inhibiting polymerization, we speculate that compound G might interact with pathways involved in secretion of mutant NS. Investigation of such pathways will possibly shed light on mechanisms of mutant NS toxicity.
|Enthalten in den Sammlungen:||Elektronische Dissertationen und Habilitationen|
geprüft am 03.08.2021
geprüft am 03.08.2021