| Summary: | <p>The Wnt pathway is a key morphogen route during embryonic development, regulating tissue organization, patterning and organ growth. In adult life, when maintained in a homeostatic range it controls stem cell self-renewal and regenerative processes, while its dysregulation promotes diseases like cancer and neurodegeneration.</p>
<p>A peculiar feature of the Wnt protein is its lipid modification by a palmitoleic acid, crucial for receptor engagement and functionality at the target cells. This acylation, however, reduces Wnt solubility, dictating the need for a dedicated machinery upstream of receptor engagement, to shield the lipid from the aqueous environment and promote the formation of concentration gradients.</p>
<p>The work presented here focused first on the elucidation of the structural and molecular mechanisms allowing Wnt to overcome this “solubility problem”. In particular, solving the structure of the Drosophila melanogaster heparan-sulfate proteoglycan Dlp in complex with a lipidated Wnt peptide, I showed that this class of membrane-anchored proteins, glypicans, has a novel role in the extracellular shielding of the Wnt lipid. The functional relevance of the interaction in modulating the extracellular Wnt spreading was confirmed by mutational and in vivo experiments in flies. The work has been published in Nature.</p>
<p>Additionally, upon thorough troubleshooting, I optimized a protocol for the recombinant production of the transmembrane protein Wntless - the main intracellular Wnt carrier - embedded in polymer-based nanoparticles, to use in future structural studies.</p>
<p>Moreover, given its importance in pathway activation, I also focused on the Wnt lipidation for therapeutic purposes in Alzheimer’s disease. To the goal, a structure-based drug development campaign was set up to find inhibitors of Notum, an extracellular modulator that specifically removes the Wnt palmitoleate from the morphogen, therefore downregulating the signalling. The work led to the identification of a patented compound with optimal pharmacological properties, currently undergoing in vivo preclinical testing.</p>
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