Yi Zeng

Neurodegenerative diseases are a growing health crisis with few disease-modifying therapies. Our lab defines the molecular mechanisms that drive neurodegeneration in amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other TDP-43 proteinopathies, and turns those insights into biomarkers and therapeutic strategies. 

A major theme of the lab is RNA metabolism. A hallmark of these diseases is dysfunction of TDP-43, an RNA-binding protein essential for gene regulation. We study why TDP-43 fails and how its dysfunction disrupts RNA processing — from splicing to alternative polyadenylation — to drive disease. Using TDP-43 as an entry point, we aim to uncover broader principles of RNA-binding protein dysfunction in neurodegenerative disease. 

A second theme is the genetic basis of neurodegenerative disease. We investigate how genetic risk factors act at the molecular level to shape disease onset and progression. For example, we recently uncovered that protective TMEM106B variants curb the harmful accumulation of a protein fragment in inherited FTD caused by GRN mutations, helping explain why some individuals are vulnerable and others resilient. 

Our lab bridges human genetics, RNA biology, and disease modeling to connect molecular defects to neurodegeneration. Ultimately, we aim to turn mechanistic understanding into therapeutic strategies.