Cell cycle inhibitors protect motor neurons in an organoid model of Spinal Muscular Atrophy

• Main Authors: Hor, Jin Hui, Soh, Eunice Shi-Yi, Tan, Li Yi, Lim, Valerie Jing Wen, Winanto, Ho, Beatrice Xuan, Fan, Yong, Soh, Boon-Seng, Ng, Shi-Yan, Munirah Mohamad Santosa
• Other Authors: School of Biological Sciences
• Format: Article
• Language: English
• Published: 2019
• Subjects: DRNTU::Science::Biological sciences; Cell Cycle Inhibitors; Spinal Muscular Atrophy
• Online Access: https://hdl.handle.net/10356/103564; http://hdl.handle.net/10220/47342
• Institution: Nanyang Technological University

Spinal Muscular Atrophy (SMA) is caused by genetic mutations in the SMN1 gene, resulting in drastically reduced levels of Survival of Motor Neuron (SMN) protein. Although SMN is ubiquitously expressed, spinal motor neurons are one of the most affected cell types. Previous studies have identified pathways uniquely activated in SMA motor neurons, including a hyperactivated ER stress pathway, neuronal hyperexcitability, and defective spliceosomes. To investigate why motor neurons are more affected than other neural types, we developed a spinal organoid model of SMA. We demonstrate overt motor neuron degeneration in SMA spinal organoids, and this degeneration can be prevented using a small molecule inhibitor of CDK4/6, indicating that spinal organoids are an ideal platform for therapeutic discovery.