Mapping the RNA granule landscape for ALS across neuronal compartments
About the Project
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that causes progressive muscle weakness and paralysis through the loss of motor neurons. A major unresolved question is why motor neurons are so vulnerable. One likely contributor is their extreme cellular architecture: motor neuron axons can extend over very long distances, placing unusual demands on RNA transport, local protein synthesis and axonal maintenance.
This PhD project will investigate how RNA granules - dynamic structures that organise RNA transport, translation and stress responses - are altered in ALS-affected human motor neurons, with a particular focus on long axons. Many ALS-linked proteins, including TDP-43 and FUS, are RNA-binding proteins associated with RNA granules, but the full landscape of RNA granules in long human motor axons remains poorly defined.
The student will use human induced pluripotent stem cell (iPSC)-derived motor neurons carrying ALS-associated changes alongside matched control lines to map the RNA granule landscape in ALS, using imaging and biochemical approaches (including iCLIP and RNAseq). These cells will be grown on the Serio lab’s Long Axon Microarray (LAM) platform, which enables human motor neurons to extend axons over approximately 1 cm while retaining access for imaging and molecular analysis. This system has already revealed ALS-relevant axonal phenotypes that are not detectable in short-axon cultures.
The project will provide training in stem cell culture, motor neuron differentiation, bioengineered long-axon systems, advanced microscopy, RNA biology, transcriptomics and bioinformatic analysis. The student will be embedded in two closely collaborating ALS research groups at King’s and the UK Dementia Research Institute, with access to strong neurodegeneration, imaging and data-analysis expertise. The work aims to identify early, compartment-specific molecular changes in ALS and to reveal candidate pathways that could be targeted to preserve motor neuron axons.
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