PhD Studentship: Investigating the role of C9orf72 in neuroinflammation in amyotrophic lateral sclerosis and frontotemporal dementia

University of Sheffield - Neuroscience

Expansions of a noncoding GGGGCC hexanucleotide repeat in the C9ORF72 gene are the most common genetic defect found to date in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). How the repeat expansion causes disease is not known, but appears to involve both loss-of-function (C9ORF72 haploinsufficiency), and gain-of-function (repeat-associated non-ATG (RAN) translation, RNA toxicity) mechanisms.

To unravel the ways in which C9ORF72 expansions cause disease it is crucial to understand the normal functions of the C9ORF72 protein.

C9ORF72 knockout mice present with varying degrees of autoimmunity and inflammation, accompanied by splenomegaly and increased expression of inflammatory cytokines, suggesting an immune-related function of C9orf72 in vivo. We and others have found that at the cellular level C9orf72 regulates autophagy, an intracellular degradation pathway that plays a fundamental role in both innate and adaptive immunity, including defence against pathogens, inflammasome activation and antigen presentation (1).

In this project we will investigate the role of C9orf72-associated autophagy in innate and adaptive immunity at cellular, tissue and whole organism levels using cell (including iPSC) and zebrafish models.

The Faculty of Medicine, Dentistry & Health Doctoral Academy Scholarships cover Home/EU fee and RCUK rate stipend for three years. Overseas students may apply but will need to fund the difference between the Home and Overseas fee from another source.

Proposed start date: October 2017

(1) Webster, C. P., Smith, E. F., Bauer, C. S., Moller, A., Hautbergue, G. M., Ferraiuolo, L. et al. (2016). The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. DOI:10.15252/embj.201694401

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Type / Role:

PhD

Location(s):

Northern England