3D in situ structures of neurodegenerative pathology

FUNDING: 10 weeks (full time, 37 hrs per week, £12 per hour, £1000 consumables)
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Madeleine Gilbert, Biology, Leeds

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Proteins that misfold into amyloid filaments within the brain are pathological features of most neurodegenerative conditions. Cryogenic electron microscopy (cryoEM) has revealed that atomic resolution structures of amyloid filaments are specific to neurodegenerative disease type, suggesting a relationship between structure and dysfunction. However, the interplay between amyloid filaments and their surrounding cellular components remains unclear. Recently, our group developed a workflow using cryogenic electron tomography (cryoET) to produce nanometer resolution 3D volumes of amyloid filaments within post-mortem Alzheimer’s disease patient brain samples. Combining cryoET with fluorescence microscopy and computational data processing techniques will allow us to interrogate the relationship between the molecular and cellular pathology of neurodegenerative diseases for the first time. During your studentship you will receive training and supervision in cutting-edge cryoET sample preparation techniques including high-pressure freezing, cryogenic fluorescence microscopy, and cryoET. You will also gain experience with the computational processing of tomographic data, segmentation of 3D tissue volumes, and data annotation. CryoET of cells and tissues is a rapidly advancing field capable of producing exciting and often beautiful insights into cell biology and pathology. Students will be expected to present their findings orally at a research day in York in September 2024.