Elucidating disease mechanisms in cerebellar ataxia using stem cell technology

The spinocerebellar ataxias (SCAs) are a complex group of neurodegenerative diseases that affect the cerebellum and result in the loss of motor coordination. No effective treatments exist for the SCAs, and there is a pressing need for better models in which to study the underlying disease-causing mechanisms and to identify potential therapies.

The aim of this project will be to develop novel stem cell-derived models to identify common pathological mechanisms in SCA that could be targeted therapeutically. The Becker group has identified several novel SCA mutations that highlight mGluR1-TRPC3-IP3R1 signaling as a key pathway affected in disease. Both research groups have developed complementary stem cell-derived and primary cerebellar models that provide unique systems to investigate the functional consequences of gene mutations affecting this pathway in the Purkinje cells, which are the neurons that are primarily affected in SCA.

The project will employ patient-derived induced pluripotent stem cells (iPSCs) as well as introduce gene mutations into iPSCs using CRISPR gene editing technology. Pluripotent stem cells will be differentiated into cerebellar neurons and three-dimensional organoids and deeply phenotyped using a combination of functional experiments including calcium imaging, super-resolution imaging, and morphological analyses. In addition, functional analyses will be carried out in primary Purkinje cells. Identified disease phenotypes will subsequently be screened for potential therapeutics.

Becker Group website: https://www.ndcn.ox.ac.uk/research/cerebellar-disease-group

Hammer Group website: https://irp.nih.gov/pi/john-hammer