HnRNPM is mislocalised from nucleus to cytoplasm in both sporadic and VCP-related amyotrophic lateral sclerosis

<h3>Background</h3> Dysfunction of RNA binding proteins (RBPs) is key to the pathogenesis of amyotrophic lateral sclerosis (ALS). Intron retention in transcripts of the RBP Splicing Factor Proline and Glutamine rich (SFPQ) is a molecular hallmark of ALS. SFPQ protein binds SFPQ intron retaining transcripts, with associated nuclear loss of SFPQ protein. However, bioinformatic predictions indicate that another RBP, heterogeneous nuclear ribonucleoprotein M (HnRNPM), is in fact the most abundant RBP bound to SFPQ IRTs. <h3>Methods</h3> Using immunohistochemistry/immunocytochemistry and confocal imaging, we investigated the subcellular localisation of HnRNPM in (i) human post-mortem spinal cord tissue from sporadic ALS cases, and (ii) human induced pluripotent stem cell derived motor neurons (hiPSC-MN) from VCP mutation related ALS. <h3>Results</h3> We report that HnRNPM is mislocalised from nucleus to cytoplasm in both sporadic ALS post-mortem spinal cord tissue, and in hiPSC-MNs from VCP-related ALS. Analysis of publicly available CLIP data confirms HnRNPM as the most abundantly bound RBP to the SFPQ IRT. <h3>Conclusion</h3> We predict that HnRNPM’s sequestration by SFPQ IRTs and mislocalisation results in loss of its nuclear functions in RNA regulation in ALS. HnRNPM could be a target for manipulation to treat ALS, for example with techniques to reverse pathological mislocalisation.