Inhibition of acid sphingomyelinase increases SMN levels and connects sphingolipid metabolism to Spinal Muscular Atrophy

Abstract

Spinal Muscular Atrophy (SMA) is a moderately rare disease that causes progressive motor neuron degeneration and presents the highest neonatal death rate of all human genetic diseases. It is associated with the deletion or mutation of the SMN1 gene, encoding the SMN protein, mainly involved in the assembly of a ribonucleoprotein complex called Sm ring, essential for the splicing of mRNA molecules. In humans, there are usually multiple copies of another gene virtually identical in sequence, SMN2, which produces 10 % of complete SMN protein. It is known that increased expression of SMN2 improves the SMA phenotype. We have developed a multidisciplinary protocol, by which negative regulatory genes of SMN2 were discovered through an in silico approach based on analysis of gene expression profiles obtained from public transcriptomics experiments. We then knockdown these candidate genes in a Caenorhabditis elegans strain where the amount of SMN can be measured by fluorescence temporally and spatially. Thus, we have found that when a homolog of human SMPD1, a gene involved in sphingolipid metabolism, is inhibited by RNAi or specific drugs, SMN levels increase. We have also used motor neuron cultures of SMA patients, finding that the levels of SMPD1 mRNA and protein are increased in these cells. Furthermore, when they are treated with the SMPD1 inhibitor clomipramine, SMN levels also increase and a significant decrease in neurite degeneration is observed. Those results propose new therapeutic avenues for this devastating disease and represent a new method of finding modifiers and drugs for human diseases.