Primary supervisor: Prof Kiterie Faller
Other supervisors: Dr Cecile Bénézech
Location: University of Edinburgh
Project description
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the progressive degeneration of motor neurons, leading to paralysis and death within 2-3 years. Despite the identification of mutations in over 30 genes, most patients lack a clear genetic cause, complicating targeted gene therapy development. However, all ALS patients exhibit dysregulation of common cellular pathways, making it essential to elucidate these shared pathological mechanisms to develop mutation-independent therapies.
ALS is marked by profound metabolic dysregulation, including hypermetabolism and widespread inflammation, both contributing to disease pathophysiology. There is an intricate interplay between metabolism and the immune system, a field known as “immunometabolism”. Metabolic alterations, as seen in conditions like diabetes and obesity, have been associated with immune system dysregulation, which further contributes to the development and progression of the diseases.
Given the intricate relationship between metabolism, inflammation, and neurodegeneration we hypothesise that dysregulation of immunometabolic pathways is a key driver of ALS pathology.
This project aims to map ALS progression alongside immune system metabolic alterations in the circulation and central nervous system. Using a mouse model of ALS and advanced techniques such as scRNAseq, the project will aim at evaluating the immunometabolic changes prior and after clinical sign onset. Ultimately, we hope to identify key changes in immunometabolic pathways, which could lead to the development of new mutation-independent therapies, thereby improving outcomes for patients suffering from this devastating disease.
References
Feldman, E. L. et al. (2022) Amyotrophic lateral sclerosis. Lancet 400, 1363-1380, doi:10.1016/S0140-6736(22)01272-7.
Faller, K. M. E., Chaytow, H. & Gillingwater, T. H. (2025) Targeting common disease pathomechanisms to treat amyotrophic lateral sclerosis. Nat Rev Neurol 21, 86-102, doi:10.1038/s41582-024-01049-4.
Lee, Y. S., Wollam, J. & Olefsky, J. M. (2018) An Integrated View of Immunometabolism. Cell 172, 22-40, doi:10.1016/j.cell.2017.12.025.
Weiner, H. L. (2025) Immune mechanisms and shared immune targets in neurodegenerative diseases. Nat Rev Neurol 21, 67-85, doi:10.1038/s41582-024-01046-7.
Ludolph, A. et al. (2023) Nutritional and metabolic factors in amyotrophic lateral sclerosis. Nat Rev Neurol 19, 511-524, doi: 10.1038/s41582-023-00845-8.
Suitable first degree subjects
Molecular biology, immunology, biochemistry, neuroscience, medicine, veterinary medicine
Essential/desirable skills and experience
Basic molecular biology/biochemistry lab experience
