Kayla Talabis
Investigating early phenotypes of Spinocerebellar Ataxia 1 in single-lumen cerebellum and cerebral cortex patient-derived organoids
My project studies spinocerebellar ataxia type 1 (SCA1), a devastating neurological condition caused by an inherited genetic mutation. Affected individuals experience impairments in motor ability and cognitive function, which progressively decline due to the death of neurons within the cerebellum and other brain regions including the cerebral cortex. To date, SCA1 has almost exclusively been studied within mouse models which require an exacerbated mutation to show SCA1 symptoms, limiting their application to humans. Additionally, SCA1 research largely focuses on impacts to the cerebellum, ignoring other brain regions. My project aims to address these gaps by investigating the impacts of SCA1-causing mutations (expanded CAG repeats on the ATXN1 gene) on brain development within a reproducible, patient induced pluripotent stem cell (iPSC)-derived brain organoid model of both the cerebellum and cerebral cortex. These reproducible organoid models are generated using a 3D micropatterned extracellular matrix approach previously established in the Julian Lab. This involves growing iPSCs on a surface restricted extracellular matrix droplet, producing a layer of cells that will fold over in 3D to create a single lumen structure. The single lumen structures are then grown in suspension in media that supports the development of different brain regions, and over time will form multicellular and structurally-sound 3D organoids with architecture that reflects the cerebellum or cerebral cortex. Using fluorescence microscopy, proteomic, transcriptomic and electrophysiological techniques I will evaluate potential defects in cerebellum and cerebral cortex development caused by pathogenic ATXN1 variants. This study will provide valuable mechanistic insights into early disease presentation in SCA1, which will help to elucidate potential therapeutic targets and disease signatures for early diagnosis.