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TARGETING TFEB TO CORRECT AUTOPHAGY/LYSOSOMAL DEFICITS IN PARKINSON’S DISEASE

Lead supervisor: Prof Richard Wade-Martins, Oxford Parkinson’s Disease Centre, Department of Physiology, Anatomy and Genetics (DPAG), Oxford

Commercial partner: Biogen, Cambridge, Massachusetts, USA

 

Introduction: Parkinson’s disease is the second most common neurodegenerative disorder but disease-modifying therapies are still lacking. Genetics and pathology strongly implicate lysosomal and autophagy dysfunction in Parkinson’s, making TFEB, a master-regulator of lysosomal biogenesis, an attractive target as a potential therapeutic. Importantly, activation or overexpression of TFEB prevents neurodegeneration and rescues Parkinson’s related autophagy/lysosome deficits. Despite increasing interest in this target, the pathways involved in TFEB function in Parkinson’s remain poorly understood, particularly in human neurons. This project will assess the effect of Parkinson’s mutations on TFEB activity and regulation to better understand the molecular pathways of neurodegenerative diseases.

Project details: To address this, and advance TFEB as a therapeutic target, the project will have three Aims. We will first characterize TFEB localization, phosphorylation and expression levels in dopamine neurons derived from induced pluripotent stem cells (iPSC) from Parkinson’s patients carrying mutations in LRRK2, SNCA and GBA, all readily available in Oxford as part of a resource of >200 iPSC lines, and study expression of genes regulated by TFEB by advanced imaging and proteomic techniques. Second, we will delineate the pathways regulating TFEB by targeted lentiviral CRISPR-Cas9 knockout and small molecule TFEB modulators. The collaboration with Biogen allows the unique opportunity of designing targeted screening libraries building on hits from previously conducted high-throughput small molecule and genome wide CRISPR screens carried out at Biogen, as well as RNA sequencing data from Parkinson’s iPSC-derived neurons produced by the Wade-Martins laboratory. Finally, we will examine the suitability of new targets/molecules for translation into patient care by assessing their ability to reverse TFEB-susceptible phenotypes. Since alpha-synuclein pathology is the defining phenotype of Parkinson’s, we will use the most successful compounds/targets to target alpha-synuclein fibril toxicity in Parkinson’s iPSC-derived dopamine neurons and in mouse models.

Research environment: The student will become part of the Laboratory of Molecular Neurodegeneration, a highly active research group comprising a mix of research fellows, post-doctoral research scientists, DPhil students and research assistants. Group members come from a mix of scientific and medical backgrounds, creating an exciting environment for research. The project will take place in the context of the Oxford Parkinson's Disease Centre (OPDC; www.opdc.ox.ac.uk), an international research Centre for Parkinson's disease headed by Professor Wade-Martins. The Centre has developed a unique interdisciplinary research environment bringing together scientists and clinicians to create a centre of excellence focused on understanding the earliest pathological pathways in Parkinson’s. Internationally-recognised scientists with strengths in stem cell models, genetics and genomics, transgenic rodent models, the structure and function of brain cells and circuits affected in Parkinson’s, magnetic resonance imaging (MRI), and analysis of protein biomarkers, are working closely with experts in epidemiology and clinical neurology who have established the Oxford Discovery Cohort of 1000 Parkinson’s patients to better understand the causes of Parkinson’s. We have built a new multi-disciplinary research program across the translational space comprising the OPDC Discovery Cohort as one of the best-characterised clinical Parkinson’s cohorts in the world, a new program in Parkinson's fMRI and laboratory biomarkers, a core expertise in molecular genetics and molecular neuropathology, the largest induced pluripotent stem-cell (iPSC) research program in Parkinson’s in Europe, and a world-leading research hub for the generation and deep-phenotyping of transgenic rodent models of Parkinson’s. The proposed collaboration will provide data in complex human neuronal and humanised rodent models to support Biogen and Oxford together advancing TFEB as a therapeutic target.

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