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

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posted on 2024-04-04, 00:51 authored by Selina Zhang

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.

History

Table of Contents

Chapter 1. Introduction -- Chapter 2. Methods -- Chapter 3. Results -- Chapter 4. Discussion -- Chapter 5. Appendix -- Chapter 6. References

Awarding Institution

Macquarie University

Degree Type

Thesis MRes

Degree

Master of Research

Department, Centre or School

Macquarie Medical School

Year of Award

2024

Principal Supervisor

Stephanie Rayner

Additional Supervisor 1

Albert Lee

Rights

Copyright: The Author Copyright disclaimer: https://www.mq.edu.au/copyright-disclaimer

Language

English

Extent

97 pages

Former Identifiers

AMIS ID: 341618