Elucidating Cellular Mechanisms of Neurodegeneration by Functional Genomics

Our research combines systems biology with mechanistic biochemistry and cell biology to elucidate mechanisms of neurodegenerative diseases. To investigate these mechanisms in the relevant human cell types, we have developed a CRISPR-based functional genomics platform in iPSC-derived neurons and glia. To reveal cellular mechanisms underlying disease-associated genes, we use genetic modifier screens in patient-iPSC derived neurons and glia. Differentiation of iPSCs into vulnerable and resilient types of neurons makes it possible to identify causal determinants of selective vulnerability to neurodegeneration. Cell-type specific gene perturbation in neuron/glia co-culture and brain organoids enables us to dissect non-cell autonomous mechanisms of neurodegeneration. We integrate our mechanistic experiments in cell-based models with the molecular characterization of patient brain tissue at single-cell resolution.