Precisely Correcting SMN Deficiency Pathways in Spinal Muscular Atrophy Using an Off-Amyloid Stabilizer

Abstract While therapies like Spinraza, Zolgensma, and Evrysdi focus on increasing SMN1 protein levels to treat spinal muscular atrophy (SMA), their effectiveness is limited and highly dependent on early intervention. This indicates that merely augmenting SMN levels may not adequately reverse the permanent pathological effects stemming from SMN1 deficiency. Our research indicates that SMA is a protein conformational disorder rather than solely a splicing disease. We found that the SMN protein contains prion-like domains located in exon 2 and exons 6-7. Due to the absence of exon 7, the SMNΔ7 variant displays reduced prion-like activity. This deficit hampers gemins and RNPs formation and leading to persistent misfolded TDP-43 and PFN1 proteins despite treatment with Spinraza and Evrysdi. Remarkably, treatment with baicalein, a prion-like folding stabilizer, enabled SMNΔ7 to form a prion-like structure, restored the assembly of gemins and RNPs, effectively cleared toxic aggregated TDP-43 proteins and alleviated symptoms in SMA models.