Investigating the Roles of the Deubiquitylation Pathway in TDP-43 Pathology in ALS/FTD

Amyotrophic lateral sclerosis (ALS), or Lou Gehrig's disease, is a progressive neurodegenerative disease caused by loss of upper and lower motor neurons in the brain and spinal cord. Frontotemporal dementia (FTD), the most common presenile dementia under the age of 60, is caused by focal degeneration of frontal and/or temporal lobes. Despite decades of intensive research, there is still no effective treatment for either disease. Pinpointing the underlying pathogenic mechanisms poses a challenge, as about 90% of ALS cases and 60% of FTD cases are sporadic. However, nuclear depletion and cytoplasmic aggregates of TDP-43 are found in about 97% of ALS cases and up to 50% of FTD cases, as well as in many patients with Alzheimer's disease. Thus, it is critically important to understand the molecular and cellular mechanisms underlying TDP-43 pathology. In this exploratory project based on some of our unexpected preliminary findings, we will use mouse models and CRISPR-edited human neurons derived from induced pluripotent stem cells to investigate how the ubiquitination/deubiquitination pathway regulates the subcellular localization of TDP-43 and TDP-43 aggregate formation. These studies will provide mechanistic insights into TDP-43 biology and may suggest novel therapeutic targets for neurodegenerative diseases characterized by TDP-43 pathology.