MECHANISMS OF HEALTH & DISEASE

Our large-scale human genomic screens and Drosophila reverse genetics studies have revealed an important role for members of the RHO GTPase and cytoskeletal dynamics pathways in neuromotor development. Mutations in these genes alter neuronal structure-function relationships and connectivity. Our work has also shown how key RHO pathway members and cytoskeletal proteins control growth cone dynamics, focal adhesions and dendritic development.

Acetyl-CoA levels integrate cellular metabolism and the response to cytotoxic insults. Although much work has focused on the role of carbon source availability in acetyl-CoA signaling, data from our lab and others indicate that distinct CoA pools exist in the cytoplasm, nucleus, and mitochondria, tightly coupling CoA synthesis and transport to fatty acid metabolism and integrated stress responses. Mutations in key genes in this process (PANK2, COASY, SLC25A42) lead to neurodegenerative diseases. Current studies in the lab are focused on understanding of cellular CoA handling and its effects on cell biology in different conditions relevant to health and disease.

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Brain organoids are miniature, stem cell–derived models that recreate key features of the developing human brain. These 'mini brain' organoid systems can be utilized to to study neurodevelopment and neurological diseases in a biologically relevant system, offering powerful new insights towards disease mechanisms, and precision therapeutic strategies. Our current work in the lab have also been leveraging iPSC-derived brain organoids to understand the impact of specific gene mutations in a developing brain. This approach allows us to better understand how certain mutations change the morphology and structure of neuronal cells.