Expanded ATXN1 alters transcription and calcium signaling in SCA1 human motor neurons derived from induced pluripotent stem cells

Dysfunction and loss of motor neurons (MNs) in the brain stem and spinal cord is hypothesized to contribute to premature lethality in spinocerebellar ataxia type 1 (SCA1) by affecting the swallowing and breathing. Despite the usefulness of SCA1 mouse models in studying pathogenesis, they have important limitations including species differences and extreme size of repeats in comparison to the repeat length present in adult SCA1 patients. Thus, to study early stages of SCA1 pathogenesis that have been shown to be most therapeutically effective in human cells, we have created a human motor neuron model of SCA1. We differentiated MNs patient and unaffected control-donated iPSCs to assess the effect of mutant ATXN1 on this vulnerable cell population with the goal to provide insight to human cellular pathology in this cell type and facilitate the development of therapies to limit pathogenesis in SCA1. Overall design: To investigate molecular mechanisms underlying SCA1 pathogenesis, we used RNA sequencing of iPSC-derived MN progenitors (pMNs) and MNs to investigate transcriptional changes.