Live Blogger: Lauren Heinzinger
Editors: Ryan Schildcrout, Brenna Saladin
This piece was written live during the 10th annual RNA Symposium, “RNA Frontiers: From Mechanisms to Medicine” hosted by the University of Michigan’s Center for RNA Biomedicine.
Huntington’s Disease (HD) is a fatal hereditary neurodegenerative disorder that typically emerges between the ages of 30 and 50. It’s a progressive disease that damages neurons in the brain that control voluntary body movement, resulting in uncontrolled dance-like movements called chorea and abnormal postures. Other symptoms of HD include changes in behavior, emotion, personality, and thinking. Despite modern medicine and all of our amazing medical advancements, there is still no cure for HD. This makes it especially important to understand the mechanisms underlying how HD damages these important neural cells.
Dr. Woodson begins her talk by explaining how it is well established that the mutated and abnormally folded huntingtin protein plays a key role in the development of HD. Specifically, the expansion of CAG triplet nucleotide repeats located within the first exon (a coding region) of the huntingtin (HTT) gene correlates with both age of HD onset and disease severity. However, she hints that the mutant HTT protein might not be the only causative factor in the HD equation.
Emerging evidence from a 2024 Nature Communications paper from the Woodson Lab suggests that another possible mechanism involves messenger RNA (mRNA). Expanded (exp) mRNA made from the mutated HTT gene (HTT mRNA) can form aggregates, called RNA foci, that trap important RNA proteins and disrupt normal RNA processing and translation. During her talk, Dr. Woodson highlights how expHTT mRNA, in addition to being a byproduct of the HTT mutation, may also be an active contributor to HD.
Now how exactly do these expHTT RNA foci physically promote HD development and progression? Dr. Woodson guides us through the logistical challenges when trying to answer that question. Historically, it has been exceedingly difficult to study the physical properties of RNA aggregation because repetitive sequences, such as the expanded CAG repeats found in expHTT mRNA, can adopt many different structures. Woodson and colleagues leverage biophysical tools, including optical tweezers, to determine how the expanded HTT RNA aggregates behave as physical molecules and contribute to HD. These optical tweezers can be thought of as an incredibly powerful but tiny two-in-one tool that allows researchers to manipulate individual RNA molecules and measure molecule length, stiffness, force, and fluctuations.
Dr. Woodson concludes her talk by explaining they have made an exciting discovery utilizing these optical tweezers: the Woodson Lab has identified a biophysical explanation for the RNA toxicity in HD. mRNAs made from mutant copies of the HTT gene form structurally “slippery” hairpins that do not unfold in one easy and clean step. Instead, the expHTT mRNA undergoes stick-slip rearrangements in which the RNA molecule shifts by plus or minus one CAG triplet at a time. This makes the expanded HTT mRNA structurally dynamic and unusually good at sticking to other RNAs, where additional optical tweezer experiments showed that partially unfolded exHTT mRNA could form intermolecular associations with other exHTT mRNAs. As the expHTT mRNA repeatedly unfolds, reshuffles, and re-pairs, it forms more stable intermediates. These intermediates may then trap proteins, such as MBNL1, which further promote additional RNA-RNA association and pairing. Ultimately, these stick-slip rearrangements may help drive the formation of toxic RNA-protein aggregates that contribute to HD pathogenesis.
Sarah Woodson is the Thomas C. (TC) Jenkins Professor of Biophysics at Johns Hopkins University, a prestigious position that recognizes her extraordinary contributions to the field of biophysics. Dr. Woodson received her PhD in Biological Chemistry from Yale University in 1987 and completed her postdoctoral research at the University of Colorado Boulder from 1987-1990. The Woodson Lab (Research | Woodson Lab | Johns Hopkins University) utilizes biophysical methods to study how RNA molecules fold into specific three-dimensional structures and how protein components of cellular complexes can form RNA-protein aggregates. Her lab has also pioneered time-resolved X-ray hydroxyl radical footprinting yielding milli-second snapshots of the RNA structure as it folds and forms complexes. Dr. Woodson received a Pew Scholar Award in 1993 and was elected to both the American Association for the Advancement of Science (AAAS) in 2010 and the President of the RNA society in 2016-2017.
Lauren Heinzinger is a second-year PhD candidate in the Department of Microbiology and Immunology. She is also pursuing a concurrent MS in Bioinformatics through the Department of Computational Medicine and Bioinformatics (DCMB). Lauren works in Dr. Robert Dickson’s lab where she studies the ecological determinants of pathogen overgrowth and pneumonia during acute lung injury. In her free time, Lauren enjoys visiting national parks, hiking mountains, reading and writing, and playing video games.
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