https:\/\/doi.org\/10.3389\/fbioe.2020.588947<\/a><\/span><\/strong><\/p>\nSynucleinopathies are a group of disorders characterized by the accumulation of \u03b1-Synuclein amyloid inclusions in the brain. Preventing \u03b1-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic intervention in these pathologies. A high-throughput screening initiative allowed us to discover ZPDm, the smallest active molecule in a library of more than 14.000 compounds. Although the ZPDm structure is highly related to that of the previously described ZPD-2 aggregation inhibitor, we show here that their mechanisms of action are entirely different. ZPDm inhibits the aggregation of wild-type, A30P, and H50Q \u03b1-Synuclein variants\u00a0in vitro<\/i>\u00a0and interferes with \u03b1-Synuclein seeded aggregation in protein misfolding cyclic amplification assays. However, ZPDm distinctive feature is its strong potency to dismantle preformed \u03b1-Synuclein amyloid fibrils. Studies in a\u00a0Caenorhabditis elegans<\/i>\u00a0model of Parkinson\u2019s Disease, prove that these\u00a0in vitro<\/i>\u00a0properties are translated into a significant reduction in the accumulation of \u03b1-Synuclein inclusions in ZPDm treated animals. Together with previous data, the present work illustrates how different chemical groups on top of a common molecular scaffold can result in divergent but complementary anti-amyloid activities.<\/p>\n
<\/p>\n
Figure 2.<\/strong>\u00a0In vitro<\/i>\u00a0analysis of the capacity of ZPDm to inhibit \u03b1-Syn aggregation.\u00a0(A)<\/b>\u00a0\u03b1-Syn aggregation kinetics in the absence (black) and presence (red) of 100 \u03bcM of ZPDm followed by Th-T fluorescence.\u00a0(B)<\/b>\u00a0Light-scattering measurements at 300 and 340 nm, in the absence (white) and presence (red) of ZPDm.\u00a0(C)<\/b>\u00a0H50Q and A30P \u03b1-Syn variants aggregation in the absence (white) and presence (blue) of ZPDm.\u00a0(D)<\/b>\u00a0Inhibition of \u03b1-Syn aggregation with different concentrations of ZPDm.\u00a0(E,F)<\/b>\u00a0Representative TEM images in the absence\u00a0(E)<\/b>\u00a0and presence\u00a0(F)<\/b>\u00a0of ZPDm. Th-T fluorescence is plotted as normalized means. Final points were obtained at 48 h. Error bars are represented as SE of mean values;\u00a0\u2217<\/sup>p<\/i>\u00a0< 0.05,\u00a0\u2217\u2217<\/sup>p<\/i>\u00a0< 0.01, and\u00a0\u2217\u2217\u2217<\/sup>p<\/i>\u00a0< 0.001. ZPDm prevents the aggregation of WT, A30P, and H50Q \u03b1-Syn variants\u00a0in vitro<\/i>, even at substoichiometric ratios.<\/span><\/p>\n","protected":false},"excerpt":{"rendered":"Front. Bioeng. Biotechnol., 16 October 2020 |\u00a0https:\/\/doi.org\/10.3389\/fbioe.2020.588947 Synucleinopathies are a group of disorders characterized by the accumulation of \u03b1-Synuclein amyloid inclusions in the brain. Preventing \u03b1-Synuclein aggregation is challenging because of the disordered nature of the protein and the stochastic nature of fibrillogenesis, but, at the same time, it is a promising approach for therapeutic […]<\/p>\n","protected":false},"author":65,"featured_media":3656,"comment_status":"closed","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[4],"tags":[],"_links":{"self":[{"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/posts\/3654"}],"collection":[{"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/users\/65"}],"replies":[{"embeddable":true,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/comments?post=3654"}],"version-history":[{"count":11,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/posts\/3654\/revisions"}],"predecessor-version":[{"id":3667,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/posts\/3654\/revisions\/3667"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/media\/3656"}],"wp:attachment":[{"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/media?parent=3654"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/categories?post=3654"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/ibb.uab.cat\/index.php\/wp-json\/wp\/v2\/tags?post=3654"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}
![\"\"](\"https:\/\/ibb.uab.cat\/wp-content\/uploads\/salvaarticulojpg.jpg\")
<\/p>\n