In ALS, a fatal disease that destroys the nerve cells controlling movement, the brain’s ability to process RNA goes awry—and this project will map exactly where and how that breakdown happens, cell by cell. The problem: researchers know that faulty RNA metabolism contributes to ALS, but they lack a detailed picture of which RNA changes actually drive nerve cell death in human tissue. Most studies have used animal models or bulk tissue, missing the cell-level differences that determine why motor neurons are especially vulnerable. The researcher will sequence RNA from post-mortem brain tissue and stem-cell-derived neurons, comparing healthy and ALS-affected cells. By tracking which RNA-splicing events go wrong and identifying the master regulators behind those errors, the work aims to pinpoint new therapeutic targets. This is fundamental science—it will not produce a drug tomorrow. But understanding the precise molecular chain of events that kills motor neurons could eventually guide treatments that slow or stop ALS progression, much as mapping genetic mutations in cancer opened the door to targeted therapies.
View original technical description
Growing evidence implicates abnormal RNA metabolism as a contributing factor to the pathobiology of amyotrophic lateral sclerosis (ALS), yet understanding remains limited in direct context of the human neurodegenerative condition. Addressing is expected to identify new disease mechanisms and therapeutic targets. I will integrate traditional and single-nuclei RNA sequencing to elucidate transcriptome-wide changes to RNA metabolism in clinically relevant post-mortem brain tissue and human induced pluripotent stem cell (hiPSC) models of ALS. Mechanistic follow-up of prioritised events will use established molecular biology, functional genomics and systems biology methods within hiPSC models. Key goals are to: - Define RNA metabolism changes in direct context of human ALS neuropathology: Molecules and networks will be characterised at region, cell and pseudo-temporal resolution. - Mechanistically dissect key RNA metabolism changes causing neural cell dysfunction: Priority will be understanding cause and consequence of non-canonical splicing reversed in ALS, and identifying intrinsic master regulators driving well-defined transcriptome signatures of motor neuron neurodegeneration. - Understand how familial ALS genetics converge on selective motor neuron vulnerability: Meta-analysing transcriptomes of perturbed single cells will functionally cluster familial ALS genes by induced cellular phenotypes. Taken together, fellowship findings will provide penetrating insights into basic neural cell dynamics relevant to ALS initiation and progression.
Plain English summaries and category classifications on this site are generated by AI and may not perfectly reflect the original research.
Is something wrong? Let us know