The project iPSCAtaxia aimed to develop state-of-the-art human cell models for the study of diseases affecting the cerebellum region of the brain. In particular, the project focused on the spinocerebellar ataxias (SCAs), a group of devastating, inherited neurodegenerative diseases for which there is currently no known cure. Research into the SCAs, and neurological disease research in general, has typically been hindered by two main challenges. The first is a lack of lack of accessible, disease-relevant cells for study, particularly given the difficulties associated with obtaining patient brain tissue. We sought to overcome this obstacle by harnessing groundbreaking induced pluripotent stem cell (iPSC) technology to establish a novel human cell model of cerebellar disease. iPSCs are stem cells derived from adult cells, which have been reprogrammed to an embryonic-like state through the introduction of genetically modified viruses. They are thus capable of differentiation into any cell type of the body following treatment with specific combinations of growth factors, offering the unique opportunity to study human neurodegeneration in the laboratory. The first research objective was thus to differentiate iPSCs into the brain cell types most affected by cerebellar disease, for use both in understanding the complex disease mechanisms underlying the SCAs, and as future drug discovery tools.
The second key challenge facing this research is the vast clinical and genetic heterogeneity of the conditions under study. To date, more than 40 causative genes have been identified for the SCAs, making the task of unravelling disease pathology and developing effective, targeted therapies particularly difficult. To help make sense of this complexity, iPSCAtaxia focused on a single candidate, the mGluR1-TRPC3 signalling pathway, defects in which have been linked to SCA1, 3, 5, 14, and 41, as well as the Moonwalker mouse model of ataxia. Since recent transcriptomic analysis of human brain tissue has also identified TRPC3 as part of a significant SCA-enriched co-expression module, we reasoned that TRPC3-mediated signalling represented a strong candidate for a common ataxia pathway, which could serve as a novel therapeutic target. The second research objective was therefore to elucidate the precise molecular mechanisms underlying such common SCA-causing disease pathways, using our disease-relevant human iPSC-based model.
The final research objective involved the adaptation of the model as a tool for therapeutic screening and drug development. Although SCAs and other neurodegenerative diseases are traditionally thought of as late-onset conditions, we and others have demonstrated developmental abnormalities in several ataxic mouse models, predominantly affecting the Purkinje cells of the cerebellum. Our iPSC-derived models, which are capable of recapitulating early developmental events in vitro, will therefore be vital in unravelling the neurodevelopmental aspects of these diseases in humans, in order to develop early-intervention therapies.
