You recently published in Science Translational Medicine from your time as a postdoc in the lab of Bal Khakh at UCLA. Please could you tell us about the rationale for this study?
Our objective was to deepen our understanding of the roles of astrocytes in Huntington’s disease (HD), which is a fatal neurodegenerative disease caused by a dominant mutation in the HTT gene. HTT is not only expressed in neurons, but also in other brain cells, including astrocytes. Astrocyte dysfunction in HD has been reported, however, we didn’t know the molecular mechanisms for it, the full extent of pathways that are altered, or if astrocyte phenotypes in Huntington’s disease are driven by the expression of mutant HTT in astrocytes or rather as a consequence of the dysfunction of the surrounding circuit.
We thought the best way to shed some light on these questions was to carry out unbiased analyses of astrocyte RNA expression in HD. We performed astrocyte specific RNA-seq from two mouse models of HD at three different stages of the disease: presymptomatic, symptomatic and late stage. We compared the results to whole tissue human HD transcriptomes and mouse proteomes of the same brain region at equivalent disease stages. In addition, we used zinc finger protein gene expression repressors to block the expression of mutant HTT specifically in astrocytes.
What were the main findings from this work?
Through deep analysis we found gene expression changes that drive the astrocyte phenotypes as previously described, e.g. alterations in calcium signalling or morphology. In addition, we identified new altered pathways and defined a gene expression signature of astrocytes in HD. Some of these pathways and, in particular, the astrocyte HD signature were dependent on mutant HTT expression, as its repression, with zinc finger proteins, rescued their changes in astrocytes. Overall, we define astrocyte alterations in HD and point at potential therapeutic targets. We even created a free search platform to explore the differential expression data here.
Finally, what’s the most important thing you have learned from your academic career so far and what do you enjoy doing outside of science?
This a difficult one because I have learned so many things. In terms of career, I have learned that if you do what you like, you are dedicated and you surround yourself by people that you admire and from whom you can learn, you will find very few limits to your aspirations.
I like being surrounded by people from many different backgrounds and origins. During my time in the USA, one of the things I enjoyed the most was the diversity - you get to know people, and eat food, from all over the world. Therefore, I love travelling, art and music. And, the older I get, the more I like nature! I quite like making and fixing things too.
Diaz-Castro, B., Gangwani, M.R., Yu, X., Coppola, G. and Khakh, B.S., 2019. Astrocyte molecular signatures in Huntington’s disease. Science Translational Medicine, 11(514), p.eaaw8546.
Adult Astrocyte RNA-Seq Explorer
Article published: 28 November 2019