Yi Zeng

Yi Zeng's research sits at the interface of RNA biology and neurodegeneration, aiming to understand why neurons die and how to stop it in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Combining human genetics, RNA biology, disease modeling, and technology development, the lab follows one disease process across scales, from molecules to cells to tissue, through three connected questions. First, how does RNA metabolism break down to drive these diseases? Second, how do genetic risk factors shape disease onset and progression? Third, how do toxic signals spread damage from cell to cell across the brain — a question the lab is building new tools to answer. Across all three, the ultimate goal is to turn mechanistic insight into new therapeutic strategies.

Yi brings deep experience in both RNA biology and neurodegenerative disease, with a track record of making once-invisible biology measurable. During his PhD at the University of Chicago, he developed CoLa-seq, a method that mapped the timing of human pre-mRNA splicing genome-wide, revealing how this timing and its genetic determinants shape which gene products a cell makes. As a postdoctoral fellow at Stanford University, he applied his RNA biology expertise to neurodegeneration, discovering that loss of TDP-43, a hallmark of ALS and FTD, disrupts RNA processing far more broadly than once recognized: it rewires alternative polyadenylation and triggers cryptic splicing that the cell's own surveillance machinery destroys and hides. Unmasking these targets reveals novel therapeutic opportunities. He also made the first connection between TDP-43 and TMEM106B, the top genetic risk factor for FTD. He further uncovered the mechanism behind its protective effect: protective TMEM106B variants curb the buildup of a toxic protein fragment in lysosomes, which helps explain why some progranulin mutation carriers develop FTD while others are spared. His work has been recognized with the John S. Spice Award in Aging and supported by the Larry L. Hillblom Foundation, the Knight Initiative for Brain Resilience, and Target ALS.