Exploring the Impact of Loss-of-Function C9ORF72 Protein on motor neuron and muscle Degeneration.

Project Advert Text

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease marked by motor neuron degeneration and neuromuscular junction (NMJ) disruption, leading to muscle atrophy. Familial ALS, making up about 10% of cases, is often caused by mutations in the C9orf72 gene, with two main mechanisms proposed: a gain-of-function from protein accumulation and a loss-of-function due to reduced C9orf72 protein. Research has mostly focused on C9orf72’s role in motor neurons, but NMJs and muscles are also critical to ALS progression. To study C9orf72’s role in a more realistic ALS model, researchers created a knockout of C9orf72 in neural progenitor cells (NPCs), which develop into motor neurons, and cultured them with human myoblasts to establish a NMJ model. This system mimics ALS more closely and helps examine motor neuron and muscle degeneration. Additionally, the drug terazosin, approved for high blood pressure, shows promise as an ALS treatment. Recent studies suggest that terazosin may be effective in treating ALS, and we plan to test its impact on ALS pathogenesis using the C9orf72-/- NMJ model. By treating this model with terazosin, we aim to assess whether the loss-of-function of C9orf72 exacerbates the pathogenesis in the model and whether terazosin can mitigate its effects.

Project Aims and Objectives

The primary goal of this project is to investigate the effects of C9orf72 loss of function on motor neurons and muscle degeneration. To achieve this, the following objectives will be carried out:

1. Establish and characterise the control and C9orf72^-/- NMJ models.
2. Examine the impact of C9orf72^-/- on NMJ model functionality (MNs and muscle degeneration).
3. Assess the effects of terazosin treatment on the functionality of the C9orf72^-/- NMJ model.

Specific Requirements of the Candidate

Applicants should have a BSc in Biomedical Science with a strong academic record, along with experience in cellular biology techniques, including tissue culture and molecular biology. A passion for research in neurodegenerative medicine and muscle cell biology is essential. The successful candidate will have the opportunity to work with cutting-edge facilities. The newly opened Dalton Building, a £117 million investment, features world-class laboratories, modern teaching spaces, and specialised research hubs designed to foster innovation and academic excellence.

Funding

This project is only available to Home students due to the nature of the funding source. The tuition fees are covered for this one-year project – no stipend is available. 

How to Apply

Interested applicants should contact Nasser Al-Shanti ([email protected]) for an informal discussion. 

To apply you will need to complete the online application form for a full-time Master’s by Research in Biological Science (or download the PGR application form).

You should also complete the Narrative CV form addressing the project’s aims and objectives, demonstrating how the skills you have maps to the area of research and why you see this area as being of importance and interest. 

If applying online, you will need to upload your statement in the supporting documents section, or email the application form and statement to [email protected]. 

Closing date: 7 March 2025

Expected start date: April 2025

Please quote the reference: SciEng-LifeSci-NS-2025- Degeneration