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

ABSTRACT: 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.

SUBMITTER: Hor JH

PROVIDER: S-EPMC6204135 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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

Hor Jin Hui JH Soh Eunice Shi-Yi ES Tan Li Yi LY Lim Valerie Jing Wen VJW Santosa Munirah Mohamad MM Winanto Ho Beatrice Xuan BX Fan Yong Y Soh Boon-Seng BS Ng Shi-Yan SY Ng Shi-Yan SY

Cell death & disease 20181027 11

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 ...[more]

PMID: 30368521

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