Role of microRNAs in flunarizine-mediated neuroprotection of motoneuron disease spinal muscular atrophy

ABSTRACT: Spinal muscular atrophy (SMA) is caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, leading to reduced SMN protein levels and widespread disruption in RNA metabolism. Despite the availability of disease-modifying therapies, clinical outcomes remain variable. Dysregulation of small non-coding RNAs, including microRNAs, has been reported in SMA, but their contribution to the disease remains poorly understood. We previously showed that flunarizine could improve the phenotype of an SMA mouse model. Here, the microRNA profile of flunarizine-treated SMA patient fibroblasts is determined by small-RNA sequencing, a subset of 30 microRNAs is validated by RT-qPCR and the effect of the differentially expressed microRNAs is analyzed using miR mimics and inhibitors in murine motor neuron-like NSC34 cells. The miR-128-3p, miR-149-5p, miR-191-5p, and miR-320a-3p are identified as novel SMA-dysregulated microRNAs. The transfection of the miR-128-3p inhibitor in NSC34 cells reduces the flunarizine-induced neurite outgrowth, a morphological hallmark of neurons. The homeodomain interacting protein kinase 2 (HIPK2) is identified as a miR-128-3p target among the differentially expressed genes by flunarizine. The transfection of miR-128-3p mimic reduces the Hipk2 mRNA levels whereas miR-128-3p inhibitor increases them. Moreover, Hipk2 expression is regulated in a genotype- and sex-dependent manner by flunarizine at early and late stages of disease in an SMA mouse model. Flunarizine changes the microRNA profile in NSC34 cells and attenuates the dysregulation of microRNAs in the SMA mouse model. We propose that an early accumulation of microRNAs can contribute to molecular dysfunctions and may represent a key-initiating event in SMA pathogenesis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE319993 | GEO | 2026/03/11

REPOSITORIES: GEO