Affiliations: Deparment of Molecular Microbiology & Biotechnology, and the Interdisciplanary Sagol School of Neurosciences, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel
Correspondence:
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Correspondence to: Daniel Segal, Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Tel Aviv 69978, Israel. Tel.: +972 3 640 9835; Fax: +972 3 640 9407; E-mail: dsegal@post.tau.ac.il.
Abstract: Tauopathies, such as Alzheimer’s disease (AD), are a group of disorders characterized neuropathologically by intracellular toxic accumulations of abnormal protein aggregates formed by misfolding of the microtubule-associated protein tau. Since protein self-assembly appears to be an initial key step in the pathology of this group of diseases, intervening in this process can be both a prophylactic measure and a means for modifying the course of the disease for therapeutic purposes. We and others have shown that aromatic small molecules can be effective inhibitors of aggregation of various protein assemblies, by binding to the aromatic core in aggregation-prone motifs and preventing their self-assembly. Specifically, we have designed a series of small aromatic naphthoquinone-tryptophan hybrid molecules as candidate aggregation inhibitors of β -sheet based assembly and demonstrated their efficacy toward inhibiting aggregation of the amyloid-β peptide, another culprit of AD, as well as of various other aggregative proteins involved in other protein misfolding diseases. Here we tested whether a leading naphthoquinone-tryptophan hybrid molecule, namely NQTrp, can be repurposed as an inhibitor of the aggregation of the tau protein in vitro and in vivo. We show that the molecule inhibits the in vitro assembly of PHF6, the aggregation-prone fragment of tau protein, reduces hyperphosphorylated tau deposits and ameliorates tauopathy-related behavioral defect in an established transgenic Drosophila model expressing human tau. We suggest that NQTrp, or optimized versions of it, could act as novel disease modifying drugs for AD and other tauopathies.
Keywords: AcPHF6 peptide, Drosophila, neurodegeneration, NQTrp compound, protein aggregation, tau protein, tauopathies
