A cast of mis-spliced genes act at the center of TDP-43-related neurodegeneration in ALS/FTD
October 9, 2025 @ 11:00 am to 12:00 pm
110 Henderson Building
University Park
Sarah Kargbo-Hill
University of Michigan
Abstract:
TDP-43 is an RNA binding protein dysregulated in nearly all cases of Amyotrophic Lateral Sclerosis (ALS) and about half of Frontotemporal Dementia (FTD). Pathological characteristics include TDP-43 cytosolic aggregation and its clearance from the nucleus. TDP-43 nuclear loss causes loss of its functions in the nucleus and is thought to be an early driver of disease. TDP-43 acts in multiple aspects of RNA metabolism, including transcription, RNA splicing, and RNA transport. However, with hundreds of RNA species altered upon TDP-43 depletion, it is unclear which effects are direct or contribute to disease. To address this, we generated multi-omic datasets, including RNA-seq and quantitative proteomics, from human iPSC-derived neurons depleted of TDP-43. We then used integrative network approaches and identified a high-confidence disease-specific subnetwork of more than 700 interacting proteins, enriched in pathways including mRNA processing, synaptic function, autophagy, and actin cytoskeleton organization. Strikingly, we found genes mis-spliced upon TDP-43 depletion were enriched throughout the network and were among those with the greatest protein reductions. These studies provide insight into the mechanisms behind the pleiotropic effects observed upon TDP-43 loss and provide novel targets for therapeutic intervention.
About the Speaker:
Dr. Sarah Kargbo-Hill is an Assistant Professor at the University of Michigan in the Molecular, Cellular and Developmental Biology department. Prior to starting her lab in 2024, she was a postdoctoral fellow at the National Institutes of Health, where she studied the normal functions of an RNA-binding protein, TDP-43, which is dysregulated in neurodegenerative diseases Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. She earned her Ph.D in Cell Biology from Yale where she studied presynaptic development and autophagy in C. elegans neurons. As an undergraduate student she attended Penn State where she was first introduced to neuronal cell biology in Dr. Melissa Rolls’ lab! She now returns to Penn State to share some of her recent work where she takes an integrative multi-omics approach using human iPSC-derived neurons to explore the how TDP-43 regulates RNA-splicing to maintain neuronal protein homeostasis.
Contact
Melissa Rolls
mur22@psu.edu