Aggregates of fragments of TDP43 (shown in green) in human cells
Evaluating Protein Quality Control in the Toxicity of TDP43 Fragments Associated with ALS and FTD
People are living longer, which increases their risk of developing neurodegenerative disorders. Such disorders can be characterized by the accumulation and aggregation of specific proteins in the brain. These aggregates often contain protein fragments produced by increases in protein cleavage or defects in protein quality control (PQC) systems such as regulated protein degradation. We do not know how all protein fragments are metabolized and how they cause toxicity to neurons. Our overall goal is to understand the effects of protein aggregates on normal cell function and to identify cellular pathways that prevent toxicity. Previously, we found that the N-degron pathway can degrade specific C-terminal fragments (CTFs) associated with neurodegenerative disorders. We also found that the N-termini of CTFs influence their metabolism, tendency to aggregate, and the morphology of their aggregates. In recent work, we found that Bcl-2-associated athanogene 6 (BAG6) interacts with CTFs linked to disease and increases their solubility. BAG6 is a component of a chaperone complex that determines the fate of unfolded proteins. In this work, we developed new methods to examine CTFs with natural N-termini in cultured neurons and in transgenic mouse models. Using these methods, we will determine how BAG6 regulates the metabolism of CTFs that are prone to aggregate. We will also establish whether aggregates of CTFs cause toxicity that leads to neurodegeneration. This project will help us better understand how protein fragments are toxic and how cellular PQC guards against neurodegeneration.
This work is supported by the National Institute of Neurological Disorders and Stroke.