Characterising the function of a novel RNA-binding protein isoform in neurons and its role in amyotrophic lateral sclerosis (ALS)

Key information

Application close date
07 February 2023, 11:59 GMT
Hours per week
36 (full time)
Application guidance
Posted 22 December 2022

Research topics

Cell Biology Gene Expression Human Biology & Physiology Neurosciences Stem Cells
Background texture taken from the lab imagery.

This is a summer student position supervised by Jacob Neeves from Rickie Patani's lab. 

Introduction to the Science

In the Patani lab we study the mechanisms driving a devastating and fatal neurodegenerative disease called amyotrophic lateral sclerosis (ALS). To do so we use induced pluripotent stem cells (iPSCs; stem cells reprogramed from patient skin cells) and differentiate these into motor neurons, the primary affected cell type. I am primarily interested in defects in the processing of RNAs, which result from the presence of ALS-causative gene mutations.

About the Project

We recently identified a novel RNA-binding protein isoform, with high potential relevance for ALS. Furthermore, we see evidence of increased expression in cellular models of ALS. However, we do not yet know what the function of this protein is, and therefore the consequence of such a phenomenon for the health of motor neurons. This raises the following question: does this protein provide protection from or contribute to degeneration of the cell? To help us address this question, we have generated artificial constructs (adeno-associated viruses) to allow us to induce increased expression of the protein isoform in question in neurons. We will also use another technique to specifically reduce its expression (e.g. RNA interference).. The student will utilise these tools to determine whether this protein contributes to key cellular phenotypes seen in ALS, including: nuclear-to-cytoplasmic mislocalisation of ALS-linked RNA-binding proteins, ER stress, and cell death. Work has the potential be included in a publication.

The student will have opportunities to learn and carry out cell culture (including iPSCs & motor neurons), molecular biology techniques (e.g. Western blotting, quantitative PCR), fluorescence imaging, and assays to measure cellular phenotypes.

About You

This project would be suitable to anyone working in biomedical sciences or medicine, with a particular interest in neuroscience / neurodegeneration and RNA biology.

References

1.         Hall, C.E., Yao, Z., Choi, M., Tyzack, G.E., Serio, A., Luisier, R., . . . Patani, R. (2017)

            Progressive motor neuron pathology and the role of astrocytes in a human stem cell model of VCP-related ALS.

            Cell Reports 19: 1739-1749. PubMed abstract

2.         Luisier, R., Tyzack, G.E., Hall, C.E., Mitchell, J.S., Devine, H., Taha, D.M., . . . Patani, R. (2018)

            Intron retention and nuclear loss of SFPQ are molecular hallmarks of ALS.

            Nature Communications 9: 2010. PubMed abstract