Inhibiting Protein Aggregation

25th July 2018.  
Daniel Segal, School of Molecular Cell Biology & Biotechnology, Tel-Aviv University

 On Wednesday the 25th of July 2018 Daniel Segal of the School of Molecular Cell Biology & Biotechnology at Tel-Aviv University will give a seminar entitled Inhibiting aggregation of amyloidogenic proteins as a strategy for treating neurodegeneration at 12.00 noon in the College Lecture theatre. Protein misfolding and aggregation are crucial steps in the onset of several, common neurodegenerative diseases and inhibiting the formation of toxic protein aggregates process may have considerable potential for therapy.  D Segal will report a series of landmark studies in which he and his colleagues have been able to identify small molecules that disrupt the formation of toxic protein aggregates, at least iunder laboratory conditions. Te poster of the lecture can be downloaded here.

My laboratory is interested in intrinsically disordered proteins, in particular disease-associated amyloidogenic proteins, and in developing means for inhibiting their harmful aggregation. Insights obtained about structural determinants that facilitate self-assembly of these proteins, such as the role of aromatic residues, serve us for developing small molecules and peptidomimetics to inhibit aggregation of these amyloidogenic proteins and disassemble of pre-existing aggregates. We evaluate efficacy of the candidate inhibitors using a series of in vitro methods, cell-based assays, and studies in transgenic animal models – Drosophila and mice. I will illustrate this approach using three examples: Tryptophan-modified naphthoquinone small molecules towards amyloid-beta and tau involved in Alzheimer’s disease; β-synuclein derived peptidomimetics towards α-synuclein involved in Parkinson’s; and a naturally occurring molecule, Mannitol, against α-synuclein with unexpected lead towards clinical trial. If time permits I will describe recent results of High Throughput screening for novel inhibitors, and the use of computational tools for understanding their mechanism of action.

Daniel Segal obtained his PhD in Genetics from the Hebrew University, Jerusalem, under the supervision of Prof. Raphael Falk, studying Drosophila developmental genetics. He did his postdoctoral studies at Harvard University, with the late Prof. William Gelbart, working on molecular genetics of the decapentaplegic developmental gene complex in Drosophila. He moved back to Israel as a scientist at the Weizmann Institute working on oncogene homologs in the fruit fly and on neurogenetics. Since 1987 he is a faculty member at Tel-Aviv University, where he is the Head of the School of Molecular Cell Biology & Biotechnology. His lab focuses on intrinsically disordered proteins, in particular disease-associated amyloidogenic proteins, and on developing means for inhibiting their harmful aggregation.

NMR structure of a-synuclein fibrils (pdf accession 2n0a).Tuttle MD et al Nat Struct Mol Biol 23:409, (2016).




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