Dr S Mizielinska, Dr D Srivastava
No more applications being accepted
Funded PhD Project (European/UK Students Only)
About the Project
Amyotrophic Lateral Sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative diseases for which no effective therapies currently exist. The most common genetic cause of both of these diseases is a repeat expansion mutation in the gene C9orf72. This mutation is responsible for around ten percent of all FTD and ALS cases, and is the most common of all neurodegenerative disease-causing mutations.
The repeat expansion mutation in C9orf72 leads to the generation of dipeptide repeat proteins, due to repeat RNA mediating its own ATG-independent translation. A study that I led shows that two of the five proteins produced from the repeat – repeating polypeptides of glycine-arginine or proline-arginine – are highly neurotoxic (Mizielinska et al., Science 2014). However, it remains unclear exactly how these proteins exert their neurotoxicity.
In vitro studies have shown that these arginine-rich polypeptides associate with proteins commonly found in membraneless organelles, such as the nucleolus and stress granules, and disrupt their normal function. These organelles are formed by proteins containing low complexity domains which allow them to undergo phase transitioning and generate a separate functional compartment. Interestingly, proteins that form the selection barriers of nuclear pore complexes also contain low complexity domains, and have been found to modify C9orf72 repeat toxicity in yeast and fruit fly models.
This PhD will therefore assess how the nucleocytoplasmic transport through the nuclear pore is affected in ALS and FTD by the dipeptide repeat proteins produced by the C9orf72 mutation. The student will acquire skills in cutting-edge techniques, such as super-resolution microscopy, neuronal and induced pluripotent stem cell culture systems, and assays for studying protein phase transitioning.
The project will form part of a larger programme of research affiliated with the newly commissioned UK Dementia Research Institute, based in the newly built Maurice Wohl Clinical Neuroscience Institute with excellent laboratory facilities.
https://www.kcl.ac.uk/ioppn/study/prospective-students/programmes-of-study/pgr/fundedresearchopportunities/PhD-ClinNeuro-SM-IOPPN-18.aspx
Funding Notes
Applicants should have (or be expected to obtain) a 2:1 or 1st class honours degree in a subject relevant to the proposed project. Applicants should also have or hope to obtain a research-based MSc degree, for which a merit or distinction level is required, or related work experience.
Funding is available for a 3-year PhD studentship to commence February 2018. The award covers academic fees (home/EU rate), a stipend (£16,553 per year) and a generous contribution towards training, conference attendance and research costs.
This studentship is open to Home/EU students only.