PROTACs for TDP-43 Degradation: A Viable Therapeutic Strategy for ALS

Amyotrophic lateral sclerosis (ALS) is a cruel neurodegenerative disease resulting in eventual paralysis, respiratory dysfunction, and death, typically within 2-4 years from symptom onset. The main pathological feature of this disease is the cytoplasmic TDP-43 protein that is present among 97% of ALS cases and 45% of frontotemporal dementia (FTD) cases. This aggregation of the pathogenic protein has exhibited cell death within mouse models and patient cortical neurons. In mouse models of ALS, the suppression of TDP-43 mutants has demonstrated decreased cytoplasmic TDP-43 with significant improvement in ALS-like symptoms. Therefore, removing TDP-43 presents a potentially valuable approach to develop new therapies to treat ALS. 

Recent advances in protein degradation systems such as proteolysis targeting chimeras (PROTACs) have demonstrated the ability to degrade proteins-of-interest. Many of these PROTACs, such as Arvina’s ARV-110, have now reached phases I and II of clinical trials and have so far yielded positive results. PROTAC's ability to degrade misfolded aggregates has only recently been illustrated in in-vitro studies of neurodegenerative diseases, with only one study demonstrating PROTAC degradation of C-terminal TDP-43 fragments (C-TDP-43) aggregates for ALS. Hence, a range of proteomics methods (such as cell culture, immunoblotting, mass spectrometry and flow cytometry) was utilised to explore the effect of PROTACs on TDP-43 degradation and further understand its use as a potential therapeutic. 

Our findings suggest that VHL-PROTACs have a significant reduction on WT-Halo-TDP-43 levels within cells. However, they do not have a profound effect on ΔNLS-Halo-TDP-43 expressing cells. We have also demonstrated that both linker length and ligand types of the PROTAC also effect TDP-43 degradation within cells. TDP-43 interactors were also identified, suggesting other possible therapeutic targets for ALS treatments. Although further investigations into these different PROTACs will be needed, PROTACs have a huge potential as an ALS therapeutic.