HD Insights™

H D I N S I G H T S HD Insights, Vol. 10 3 Copyright © Huntington Study Group 2015. All rights reserved. H D I N S I G H T S Dr. Francesca Cicchetti is a neuroscientist at the University of Laval in Québec, Canada. Her 2014 paper "Mutant huntingtin is present in neuronal grafts in Huntington disease patients," published in Annals of Neurology, 1 was selected by the HD Insights Editorial Board as one of the most influential papers of the year. Her findings suggest that mutant huntingtin (mHTT) can be transmitted through non – cell-autonomous mechanisms, and potentially implicate the immune system in HD pathology. Her discoveries are already leading to new understanding of HD pathogenesis and have the potential to identify novel targets for early HD therapies. Dr. Cicchetti recently spoke with HD Insights about her past and current research. The following is an edited transcript of the conversation. Dr. Francesca Cicchetti VITAL SIGNS NAME: Francesca Cicchetti, PhD POSITION: Professor and Researcher, Neuroscience Department, Centre de Recherche du CHU de Québec, Faculty of Medicine, Laval University EDUCATION: BS, McGill University, Montréal, QC; MS and PhD in Neuroscience, Université de Laval, Québec, QC; post-doctoral work with Ole Isacson, MD, Harvard University, Cambridge, MA HOBBIES: Travel; tango and salsa Meet the Investigator HD INSIGHTS: Can you tell us how you first became interested in HD? CICCHETTI: I was doing a PhD thesis under the supervision of Dr. André Parent, a renowned neuroanatomist based here at Laval University in Québec, and had been assigned a project on tract tracing studies in squirrel monkeys. I became very attached to the animals. I had names for each one of them and fed them bananas in the morning. When it was time to sacrifice them, I simply could not do it, I was just too emotional. I told Dr. Parent that I could not continue the project. At that time, he was also keen to initiate a human brain bank, and asked me if I would be interested in taking on this project instead. So, I began to contact pathologists, and I collected close to 500 human brains. The brain bank is still active today in distributing tissue to various research groups. Through this endeavor, I began studying the human brain: the basal ganglia in normal conditions, and then became interested in pathologies related to striatal dysfunction, such as HD. HD INSIGHTS: What were your first research experiences with HD? CICCHETTI: Our initial work focused on the characterization of striatal cell populations, and trying to understand their selective vulnerability. We were particularly interested in subpopulations of interneurons that express calcium-binding proteins. These were the very first papers that we published in the field. HD INSIGHTS: Your paper in Annals of Neurology suggested for the first time that mHTT might be transmissible from nerve cell to nerve cell. Can you discuss? CICCHETTI: I believe that this paper is our most important contribution to HD research. We were extremely fortunate, of course, to have access to this unique material, the brains of HD patients who had received fetal striatal transplants as an experimental therapy as an attempt to slow the progression of their disease – a trial that was initiated by Thomas Freeman at the University of South Florida. Our paper demonstrated the presence of the mHTT protein within the grafted tissue a decade post-transplantation. We did not see this in early time points following transplantation. The mutant protein was found within the extracellular matrix of the grafted tissue, not specifically within grafted cells. However, we also saw mHTT aggregates in cells associated with blood vessels as well as in perivascular macrophages within the cerebral tissue of the transplanted HD patients. When we first submitted the paper reporting this data, it was clear that the reviewers were interested in this finding, but did not quite believe it. We used every technique we could possibly use on human postmortem tissue—immunohistochemistry, (continued on Page 4...)

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