This #TraineeTuesday, we are excited to introduce Denethi, a graduate student in the Guo Lab! She has been awarded the prestigious Tom & Joan Steitz Fellowship, making her the youngest and only female graduate student recipient this year.
Winning this fellowship [...] opens up avenues for contributing to the esteemed community of Yale RNA scientists and offers a platform to learn from and inspire future generations of RNA scientists. As an international student ineligible for many federal grants and fellowships, internal fellowships like this provide invaluable support and affirmation of my research endeavors.
Additionally, Denethi was selected as this year’s nominee for the BBS-wide Edward L. Tatum Fellowship by the Yale Department of Neuroscience. She also recently co-authored a manuscript with Dr. Amy Arnsten, which highlights the protein pTau217 as an early biomarker of neurodegeneration in non-human primates – an important discovery in the study of Alzheimer’s Disease and dementia.
Denethi is also the first author of a manuscript currently pending publication in Developmental Cell. The paper investigates how nucleotide repeat expansions — a genetic phenomenon where the building blocks of DNA is repeated multiple times within a gene — disrupt the transport of RNA along the axon. These disruptions interfere with protein translation in neurons, ultimately leading to damage or degeneration of axons, which is a hallmark of many neurodegenerative diseases.
Denethi hails from Sri Lanka and completed her undergraduate studies at The Ohio State University. During her junior year, she was drawn to Yale by its renowned research community and conducted research with Pallavi Gopal, PhD. After graduating from college, Denethi returned to the Gopal Lab as a postgraduate researcher, delving into the molecular mechanisms underlying neurodegenerative diseases. Her work focused on ALS (amyotrophic lateral sclerosis) and frontotemporal dementia, both characterized by the mislocalization and aggregation of TDP-43, an RNA-binding protein essential for RNA processing after transcription. There, she pinpointed a previously unknown mechanism for the degeneration of axons seen in ALS, which involves a protein called Ataxin-2.
Denethi is now a graduate student in the lab of Junjie Guo, PhD, where she continues to advance research in neurodegenerative diseases. The team discovered the mechanism by which an intronic nucleotide repeat expansion (NRE) — a genetic mutation characterized by an abnormal increase repeated nucleotide sequences within the non-coding region of a gene — leads to the production of toxic dipeptide repeat proteins in ALS and frontotemporal dementia.
My journey at Yale has been the most enriching and fulfilling experience of my life.
From an undergraduate intern to a postgraduate researcher, and now a graduate student at Yale, Denethi believes the true highlight of her research experience is the vibrant and inspiring community within Yale neuroscience.
Among my truly remarkable mentors, Drs. Guo, Pereira, Gopal, Arnsten, and Greer stand out as beacons of inspiration and guidance. They are not just mentors to me — they are the embodiment of the best thing that has happened to me in my academic pursuits. Their collective wisdom, encouragement, and knowledge have not only shaped my academic journey but have also deeply influenced the person I am today. The support extended by my fellow colleagues in the lab has not only deepened my understanding of science but has also imparted invaluable life lessons that extend far beyond the laboratory walls. Their belief in my potential fuels my passion for scientific inquiry, and for that, I am eternally grateful.
Through these experiences, Denethi has developed a strong passion for stem cell models and the use of patient-derived cells, as they provide her with the opportunity to simulate how a patient’s neurons respond to specific treatments outside of the body with minimal intervention. According to Denethi, this technique can advance translational research and therapeutic design in neurodegenerative diseases. Looking ahead, she is eager to leverage stem cell models and “brain in a dish” organoids to further unravel the pathophysiology of neurodegenerative disorders. Her ultimate goal is to build a career focused on translating benchside discoveries into clinically impactful therapies, particularly through developing patient-specific neuronal models for drug screening.
“Neurodegeneration involves numerous contributing factors,” Denethi explained. “While many of these factors that contribute to neuronal disease have been identified, the underlying cause of eventual neuronal death remains elusive. The essence of my research lies in unraveling the complex mechanisms driving neurodegeneration. By elucidating the molecular underpinnings of RNA missplicing and protein aggregation in neuronal demise, my research contributes crucial insights and fills missing puzzle pieces needed for therapeutic interventions in neurodegenerative diseases.”
Another goal of Denethi’s is to mentor fellow international students.
It really feels like an uphill battle for international students like me to be able to perform research at this level, but Yale has been so welcoming and resourceful. I hope to inspire and mentor other international students to chase their dreams and continue to push scientific boundaries.