Embelin as Lead Compound for New Neuroserpin Polymerization Inhibitors.

Cristina Visentin,Francesca Bonato,Daniele Passarella,Loana Musso,Stefano Ricagno,Claudia Moriconi,Elena Miranda,Sabrina Dallavalle,Luca Broggini,Rosaria Russo,Martino Bolognesi

doi:10.3390/life10070111

Cristina Visentin, Francesca Bonato + Show 9 more

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https://doi.org/10.3390/life10070111

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Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a severe and lethal neurodegenerative disease. Upon specific point mutations in the SERPINI1gene-coding for the human protein neuroserpin (NS) the resulting pathologic NS variants polymerize and accumulate within the endoplasmic reticulum of neurons in the central nervous system. To date, embelin (EMB) is the only known inhibitor of NS polymerization in vitro. This molecule is capable of preventing NS polymerization and dissolving preformed polymers. Here, we show that lowering EMB concentration results in increasing size of NS oligomers in vitro. Moreover, we observe that in cells expressing NS, the polymerization of G392E NS is reduced, but this effect is mediated by an increased proteasomal degradation rather than polymerization impairment. For these reasons we designed a systematic chemical evolution of the EMB scaffold aimed to improve its anti-polymerization properties. The effect of EMB analogs against NS polymerization was assessed in vitro. None of the EMB analogs displayed an anti-polymerization activity better than the one reported for EMB, indicating that the EMB–NS interaction surface is very specific and highly optimized. Thus, our results indicate that EMB is, to date, still the best candidate for developing a treatment against NS polymerization.

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The serpinopathies are a group of conformational diseases characterized by the accumulation of a misfolded member of the serpin superfamily into large inclusion bodies that cause cellular toxicity [1]
We recently reported the ability of embelin (EMB) to prevent NS polymerization and to dissolve preformed NS polymers [25]
In the presence of 1.5 mM EMB, the high-molecular weight polymeric forms (Pol) were not observed, but smaller oligomers eluted at 12.3 mL (Olig12), in keeping with the effect we previously reported in

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Introduction

The serpinopathies are a group of conformational diseases characterized by the accumulation of a misfolded member of the serpin (serine protease inhibitor) superfamily into large inclusion bodies that cause cellular toxicity [1]. Familial encephalopathy with neuroserpin inclusion bodies (FENIB) is a member of this group of pathologies. FENIB is a rare and autosomal dominant genetic disease with fatal outcome [2], which presents as consequence of point mutations in the SERPINI1gene coding for neuroserpin (NS) [3,4,5,6]. The amount of inclusions and the severity of the pathology, as well as the date of onset, depend on the specific mutation present in the patient [4,7]. There are six reported mutations responsible for FENIB: S49P, L47P, S52R, H338R, G392E and G392R [2,4,5,6]

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