Whole-transcriptome sequencing in neural and non-neural tissues of a mouse model identifies miR-34a as a key regulator in SMA pathogenesis.

Spinal muscular atrophy (SMA) is a severe neurodegenerative disorder caused by deficiency of survival of motor neuron (SMN). While significant progress has been made in SMA therapy by rescuing SMN expression, limited knowledge about SMN downstream genes has hindered the development of alternative therapies. Here, we conducted whole-transcriptome sequencing of spinal cord, heart, and liver tissues of a severe SMA mouse model at early postnatal ages to explore critical coding and non-coding RNAs (ncRNAs). A large number of differentially expressed RNAs (DE-RNAs) were obtained, including 2,771 mRNAs, 382 microRNAs (miRNAs), 1,633 long ncRNAs, and 1,519 circular RNAs. Through in-depth data mining, we unveiled deregulation of miR-34a in all tissues. Analysis of competitive endogenous RNA networks of DE-RNAs identified multiple novel targets of miR-34a including Spag5 mRNA, lncRNA00138536, and circRNA007386. Further in vitro studies using mouse myoblast and human cardiomyocyte cell lines showed that knockdown of SMN upregulated miR-34a-5p and overexpression of miR-34a-5p alone disrupted cell-cycle progression through regulating its targets, recapitulating gene expression patterns observed in cardiac tissue of SMA mice. Our results identified a critical miRNA involved in SMA pathology, which sheds insights into the molecular basis of widespread tissue abnormalities observed in severe forms of SMA.