A single faulty protein, TDP-43, is gumming up the repair machinery inside the nerve cells that control movement, and this project will track exactly how that breakdown kills them. Motor neurons are among the body’s largest cells, with signal-carrying axons that stretch from the spinal cord to the muscles. When an axon gets damaged—which happens routinely—it needs to quickly make new proteins from RNA templates that must travel long distances from the cell’s nucleus. TDP-43 normally helps shuttle those RNA templates to the right place. In ALS, TDP-43 goes rogue, and the repair response fails. This project will use specially bred mice carrying ALS-linked TDP-43 mutations, along with patient-derived stem cells and donated post-mortem tissue, to watch the molecular chain of events unfold from the earliest pre-symptomatic stage through paralysis. This is fundamental science. It will not produce a drug next year. But understanding exactly which RNAs and proteins are missing or mislocalised in damaged axons—and when—gives drug developers concrete targets to aim at. Similar fundamental work on protein aggregation in Parkinson’s disease, for example, eventually led to clinical trials for therapies that clear those aggregates. A clear molecular map of the TDP-43 damage pathway could do the same for ALS.
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Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease (MND), is a devastating neurodegenerative disorder that causes progressive loss of MNs, leading to impaired muscle function and paralysis. ALS is incurable and leads to death, usually caused by the inability to breathe, on average only 3 years after diagnosis, with a lifetime risk of about 1 in 400. Motor neurons (MNs) are the nerve cells that send signals from the spinal cord to our muscles. They are amongst the largest cells in the body, with their cell soma located in the spinal cord and its fiber (called 'axon') projecting outside to the muscles. All cell compartments, including axons, need a constant supply of newly synthesised proteins in order to function properly. On some occasions, for example when responding to an unpredicted event as cell damage, new and different proteins are absolutely needed to re-establish cell functionality and long term survival. This is particularly challenging for axons, as the RNA for these proteins, which is essential to make them, may need to be synthesized very far away in the nucleus. Multiple lines of evidence indicate that one of the crucial players in the disease mechanism of ALS is a protein called TDP-43, which is important for the specific transport of RNA to different locations in the axons and in the response of cells to stress and damage. In this Fellowship, I will test how TDP-43 impacts on the response of MNs to damage in the axons, and the relevance of this response pathway in ALS. To do so, I will combine novel mouse models of disease and patient cell lines with state-of-the-art biological tools that will allow the investigation of these very specific functions. In particular, we have developed novel strains of mice that carry specific mutations in the mouse TDP-43 gene and, as a result, develop crucial features of ALS. These mouse models of ALS will allow us, by looking over time at pre-symptomatic mice and at mice with overt ALS symptoms, to identify the molecular and cellular changes occurring during disease progression. Using an innovative and fully integrated approach, we will analyse the disease phenotype of these mice with new molecular biology and microscopic techniques to identify which types of RNAs and proteins are present in different MN regions, including the axon, and how these change in response to damage. I will therefore be able to investigate the cellular alterations triggered by TDP-43 in axonal damage response by studying: 1. MNs grown in special culture dishes where the axons are separated from the cell bodies; 2. The axons and their damage response in wild type and mutant mice; and 3. By validating our results in MNs derived from patient-induced stem cells and using post mortem brain samples donated to research by ALS patients. In summary, this project will contribute to understand how changes in TDP-43 impacts on MN survival. This long-awaited information is essential to develop effective therapeutics for motor neuron disorders.
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