Investigating the role of C9ORF72 in motor neuron diseases

We are looking for highly motivated candidates to explore the role of C9ORF72 in neurodegeneration associated with amyotrophic lateral sclerosis (ALS). ALS is a motor neuron disease characterised by progressive injury and death motor neurons in the brain and spinal cord. Recent reports suggest that C9ORF72 hexanucleotide intronic repeat expansion cause ALS with high prevalence in both familial and sporadic cases. The C9ORF72 gene is located on chromosome 9p (9p21) and encodes twelve exons, with three transcription variants, and two possible protein isoforms, termed a and b. The normal expansion typically comprises a fewer than 30 of GGGGCC repeats. Pathogenic expansions consists of hundreds to thousands repeats. RNA foci are observed in fibroblasts and CNS of patients with C9ORF72 expansion, suggesting defects of RNA metabolism. Despite the significant progress in C9orf72 research, the exact function of the C9orf72 protein remains unclear. Thus, further research efforts aimed at better understanding the role of C9ORF72 protein are of the utmost importance to enable therapeutic development for ALS.

The successful candidate will join a team of several postdocs and technicians and he/she will benefit from their support and expertise. The student will use/learn cell culture, basic molecular biology techniques, CRISPR/Cas9 approach, iPS -derived from ALS patients, viral vector design/production and in vivo work. Gene manipulation in the cell culture model will be made using viral vectors and CRISPR Cas9 to modulate C9ORF72 gene. The student will attend several courses/workshops including Home Office course for in vivo experimentation. We support our PhD students to attend and present their research findings at national and international conferences.

The proposed work will be undertaken within the Sheffield Institute for Translational Neuroscience (SITraN: http://www.sitran.org/people), a world class environment for translational research. SITraN was specifically designed to bring together a multidisciplinary team of scientists, bioinformaticians and clinicians in order to effectively translate basic science discoveries into potential neuroprotective therapies for patients with MNDs. SITraN hosts state-of-the-art laboratories and equipment with a collaborative, multi-disciplinary environment including expertise in basic neuroscience, gene therapy, clinical neurology, neuropathology, computational biology, high throughput genomics and clinical trials methodology. The dedicated research accommodation encompasses tissue culture and gene therapy suites, facilities for live cellular imaging, confocal microscopy, laser capture microdissection, next generation sequencing, gene expression arrays and small molecule drug screening. We have an inter-faculty computational biology team embedded within SITraN that integrates and analyses our high dimensional data to iteratively develop systems models of disease.

The assembled team of supervisors has significant track record in studying the biochemistry of neurological disorders, vector design and evaluation in pre-clinical studies using in vivo models of neurodegeneration. This is reflected in high impact publications in prestigious journals such as Nature, Nature Medicine and Science Translational Medicine, PNAS. For further info about the project please contact Prof Mimoun Azzouz ([Email Address Removed]) and Dr Guillaume Hautbergue ([Email Address Removed]).