The heterogeneous ribonuclear proteins (hnRNPs) are a family of RNA-binding proteins that post-transcriptionally regulate gene expression, by controlling mRNA stability, localization, transport and alternative splicing. Many RNA-binding proteins implicated in mRNA trafficking in motor neurons (MNs) have shown to interact with Survival Motor Neuron (SMN) protein, which is part of the SMN complex. Mutations in SMN cause Spinal Muscular Atrophy (SMA), a motor neuron specific disorder; the reasons for the selective vulnerability of motor neurons linked to SMN reduction remain unclear. hnRNPQ is one of the major component of the SMN complex, it directly interacts with the Tudor domain of SMN and is associated with MNs specific mRNAs.
hrp-2, the C.elegans homolog of hnRNPQ, is an essential gene widely expressed through all stages. We observed that
hrp-2(
ok1278) null animals arrest as larvae similarly to
smn-1(
ok355) null mutants. To investigate if
hrp-2 has a role in vivo in
smn-1 pathway, we overexpressed
hrp-2 in all neurons in a SMA model where
smn-1 is specifically silenced in D-type MNs (MNs RNAi) (Gallotta et al. HMG, 2016). The pan-neuronal overexpression of
hrp-2 rescues the degeneration of MNs observed in
smn-1(MNs RNAi) and reduce the number of apoptotic MNs (Rizzo et al. Brain 2019). Interestingly, the defect in backward locomotion shown by
smn-1(MNs RNAi) animals is fully rescued by
hrp-2 expression in neurons. To address how hnRNPQ/hrp-2 works in Smn1 pathway we performed an RNA-seq of MNs generated from SMA patient iPSCs. By motif enrichment analysis of differentially expressed/spliced genes in SMA and controls, we identified the RNA motif 7, which is specifically recognized by hnRNPQ, as the most significantly enriched one. Moreover, we identified new neuron-specific genes altered in SMA MNs and possessing motif 7, that can be involved in MNs survival and function and whose validation in C.elegans is ongoing. Our data suggest that SMN/hnRNPQ complex through RNA motif 7 may account for the selective motor neuron degeneration and represent a potential therapeutic target.