Spinocerebellar ataxia type 1 (SCA1) is a dominantly inherited neurodegenerative disease caused by the expansion of a polyglutamine (Q) repeat tract in the protein ataxin-1 (ATXN1). Beginning as a cerebellar ataxic disorder, SCA1 progresses to involve the cerebral cortex, hippocampus, and brainstem. Using SCA1 knock-in mice that mirror the complexity of the human disease, we report a significant decrease in the capacity of adult neuronal progenitor cells (NPCs) to proliferate. Remarkably, a decrease in NPCs proliferation can be observed in vitro, outside the degenerative milieu of surrounding neurons or glia, demonstrating that mutant ATXN1 acting cell autonomously within progenitor cells interferes with their ability to proliferate. Our findings suggest that compromised adult neurogenesis contributes to the progressive pathology of the disease particularly in areas such as the hippocampus and cerebral cortex where stem cells provide neurotropic factors and participate in adult neurogenesis. These findings not only shed light on the biology of the disease but also have therapeutic implications in any future stem cell-based clinical trials.
Bibliographical noteFunding Information:
We thank the members of the Opal lab for their intellectual input. We thank Jessica Huang for her help with the histopathology and mouse genotyping. MC was supported by startup funds for the Institute for the Translational Neuroscience and Minnesota Medical Foundation, while PO received grant support from the US National Institutes of Health (1R01 NS062051 and 1R01NS082351).
© 2016, Springer Science+Business Media New York.
- Spinocerebellar ataxia type 1