Nathan Riguet wins the 2022 BMI thesis prize

Nathan Riguet. Credit: EPFL

Nathan Riguet. Credit: EPFL

The 2022 prize for best PhD thesis from EPFL’s Brain Mind Institute has been awarded to Dr Nathan Riguet.

Every year since 2011, the Brain Mind Institute at EPFL awards a prize for the best PhD thesis. The selection is made by the committee and the Director of the EPFL PhD program in Neuroscience (EDNE), and takes into account the appraisals and evaluations from the experts of the PhD theses committees, based on the scientific work of the PhD graduates.

This year, the BMI Best Thesis Prize has been awarded to Dr Nathan Riguet, who carried out his doctoral work under the supervision of Professor Hilal Lashuel. His thesis is titled “Disentangling the mechanisms of inclusions formation in Huntington's disease: The need for more disease-relevant models”.

Professor Johannes Gräff, the EDNE program’s director says: “Nathan Riguet's thesis is highly original and provides novel insight into the mechanisms of protein aggregation in neurodegenerative disease, with a particular focus on Huntington’s disease, but with potentially far-reaching consequences to other types of proteinopathies. The advances in the thesis provide a new way to understand the nature of these aggregates and call into question the relevance of current approaches to understand the processes of aggregate formation, constitution and impact upon cellular function. These findings lay the foundation for exploring novel therapeutic targets to treat neurodegeneration. What is more, the final thesis document and presentation were excellent. Indeed, the written document was of such high quality that it was suggested on the spot that the introduction chapter could and should be published as a stand-alone review manuscript. Taken together, based on the scientific discoveries as well as of an exceptionally high-quality thesis work and defense, Nathan Riguet is the worthy recipient of the 2022 BMI Prize.”

Dr Riguet will be presenting his thesis on 21 December 2022.

Project abstract
Despite the fact that the gene responsible for Huntington’s disease (HD) is known, we still do not understand the underlying mechanisms leading to neurodegeneration and death. Identifying and understanding the mechanisms controlling mutant huntingtin (mHtt) aggregation and inclusion formation using different cellular and animal models is crucial to elucidate the molecular mechanisms underpinning the disease and to develop effective treatments to prevent or slow the progression of HD.

At the mechanistic level, our work shows that mHtt aggregation and inclusion formation in the cytosol and nucleus occur via different mechanisms and lead to the formation of inclusions with distinct biochemical and ultrastructural properties. We show that mHtt cytoplasmic inclusion formation occurs first with the rapid formation of a dense fibrillar core driven predominantly by intermolecular interactions involving the polyQ domain via phase separation-like mechanisms. A second phase is associated with the recruitment of soluble mHtt, fibril growth, and the active recruitment and sequestration of lipids, proteins, and membranous organelles. Using primary neurons, we demonstrated that neuronal intranuclear inclusions evolve from small aggregates to large granulo-filamentous inclusions associated with cellular toxicity over time.

Finally, we would like to emphasize that our comparative analysis of tag-free and GFP-tagged mutant mHtt aggregation and inclusions formation will inform future efforts to develop models that reproduce HD pathology more faithfully and underscore the need for developing label-free techniques to investigate disease-relevant mechanisms that underpin inclusion formation.