Do distinct C-terminal fragments of TAR DNA binding protein (TDP43) behave differently?

Identification: Kasu, Yasar Arfat


Description

 

Do distinct C-terminal fragments of TAR DNA binding protein (TDP43) behave differently?
 
Yasar Arfat T. Kasu, Samrawit Alemu, Christopher S. Brower
Department of Biology, Texas Woman's University, Denton, TX
      
C-terminal fragments of the TAR DNA-binding protein-43 (TDP43) have been identified as major components of intracellular aggregates associated with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). It is unclear if these fragments play a causative role in disease or are epiphenomenal.  Owing to numerous cleavage sites within TDP43, a variety of C-terminal fragments can exist with distinct N-termini.  However, little is known regarding the cellular effects of different TDP43 fragments or if they are differentially metabolized.  Previously, we found that C-terminal fragments of human TDP43 accumulate in the absence of the N-end rule pathway of the ubiquitin proteasome system and that their degradation requires Arginyl-tRNA-protein transferase 1 (ATE1) (Brower et al., 2013).  Here, we examined two specific fragments of TDP43 (TDP43219-414 and TDP43247-414) that are ~85% identical but differ at their N-terminus.  We found that TDP43247-414 is degraded exclusively by the N-end rule pathway, whereas an additional pathway participates in the degradation of TDP43219-414.  Consequently, these fragments differ in their propensity to aggregate.  Interestingly, in the absence of their degradation, TDP43219-414 and TDP43247-414 form morphologically distinct cytoplasmic aggregates.  In efforts to understand the molecular basis for these differences, we used mass spectrometry to identify proteins interacting with soluble and aggregated TDP43219-414 and TDP43247-414, and used gene ontology analysis to classify associated proteins based on biological process.  We found that, in addition to proteins involved in RNA metabolism, the soluble C-terminal fragments of TDP43 associated with proteins involved in protein folding, whereas TDP43 aggregates were enriched in proteins involved in cellular respiration.  This work i. suggests that the aggregation of C-terminal TDP43 fragments may influence cellular metabolism; and ii, illustrates that differences in the N-terminus of otherwise similar aggregation-prone fragments can have profound effects on fragment behavior.  
 
This research is supported by the National Institute of Neurological Disorders And Stroke of the National institutes of Health under Award Number R15NS095317 as well as the Texas Woman's University Research Enhancement Program
 

 

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