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

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.