Unraveling the Aggregation of TDP43 Fragments Associated with ALS and FTD: Insights into Protein Quality Control Mechanisms and Cellular Vulnerability

Texas Woman'S University, Denton TX

Investigators

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Abstract

Project Summary As life expectancy increases, so does the prevalence of Alzheimer’s disease (AD) and AD-related dementias (ADRD), posing significant healthcare burdens. These conditions are linked to aggregates of specific proteins or proteolytic fragments in central nervous system cells. For example, C-terminal fragments (CTFs) of the TAR DNA-binding protein 43 (TDP43) are the primary components of protein inclusions in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and are also associated with ADRD. These fragments are generated by increased protein cleavage or defects in protein quality control (PQC) systems, such as the pathways involved in protein degradation. Despite ongoing research, the processes that produce toxic protein fragments and the cellular mechanisms that respond to them are not fully understood. Our lab specializes in protein degradation through the ubiquitin-proteasome system (UPS), particularly with respect to proteolytic fragments. We have studied multiple disease-linked CTFs of TDP43 and found that their N-termini, determined by cleavage sites, influence their metabolism, aggregation potential, and toxicity. Additionally, we have identified two distinct UPS pathways that recognize specific features of these fragments and help protect cells from aggregation. This suggests that a cell’s vulnerability to CTF aggregation depends on how the fragment is generated and the PQC pathways active within the cell. In this project, we will investigate a third potential mechanism for removing aggregation-prone fragments linked to neurodegeneration and assess the susceptibility of different brain cell types to protein cleavage and aggregation. This research will deepen our understanding of neurodegenerative diseases and provide opportunities for student involvement in cutting-edge research at Texas Woman’s University.