Identification of novel therapeutic targets for TDP-43 proteinopathies

Summary

Understanding how TDP-43 pathology drives neuronal dysfunction to guide the development of improved therapies for neurodegenerative diseases.

What are we doing?

TDP-43 is a nuclear protein known to play a crucial role in RNA processing and regulation. Its mislocalisation and aggregation have been implicated in several neurodegenerative diseases and its pathology is present in up to 97% of patients with amyotrophic lateral sclerosis and a large proportion of individuals with frontotemporal dementia and Alzheimer’s disease.

Given the considerable challenges posed by these conditions and the lack of effective therapeutic options, it’s important to research the mechanisms associated with TDP-43 to help develop targeted interventions and advancements in treatments.

Our goal is to explore the genetic landscape associated with TDP-43 mislocalisation and aggregation to pinpoint genes that are dysregulated in the presence of such pathology, and validate their functional significance to help develop targeted therapies.

How are we doing it?

We have developed an innovative in vitro model that successfully induces TDP-43 mislocalisation and aggregation in human motor neurons derived from induced pluripotent stem cells, without having to introduce genetic mutations or chemical stressors. This provides a controlled and reproducible system to mimic the TDP-43 pathology observed in neurodegenerative diseases and study its underlying mechanisms. We plan to integrate this model with pooled CRISPR screens, a powerful tool that will allow us to systematically identify genes that may be directly involved in or modulate TDP-43 mislocalisation and aggregation. This combined approach seeks to uncover key genetic contributors and potential therapeutic targets relevant to neurodegenerative diseases marked by TDP-43 pathology.

What happens next?

The genes identified can serve as potential drug targets and can be explored for therapeutic purposes through the use of small molecules or antisense oligonucleotides, offering diverse avenues for the development of targeted interventions to mitigate the impact of TDP-43 pathology in neurodegenerative diseases.

Supervisors

Dr Akshay Bhinge (primary supervisor)

Prof Jonathan Mill (co-supervisor)

Prof Clive Ballard (co-supervisor)