Prion-Like Domain Dysfunction in SMN1 Initiates Aberrant hnRNP Assembly, Multiple Protein Aggregation and Causing Spinal Muscular Atrophy

Abstract

Abstract Many proteins linked to neurodegenerative diseases, such as tau, TDP-43, and alpha-synuclein, contain specialized segments known as prion-like low-complexity (LC) domains. Although inherited mutations in these proteins often occur within these domains, their exact role in neuropathology remains unclear. Spinal muscular atrophy (SMA), caused by loss of SMN proteins, is an autosomal recessive disease involving motor neuron degeneration. Herein, we found that SMN1 contains a prion-like domain in exons 6-7. Loss of the prion-like domain of SMN1 not only causes condensatopathy of gems but also disrupts the homeostasis of prion-like hnRNPs and triggers the protein aggregation of prion-like partners of SMN1, i.e., TDP-43 and PFN1, and motor neurodegeneration. Interestingly, SMN2, a near-identical gene, lacks this domain. We found that treating cells with a drug called baicalein enables SMN2 to adopt a prion-like structure, restoring phase condensation, eliminating TDP-43 and PFN1 protein aggregates, and improving SMA symptoms in models. In summary, the loss of SMN1's prion-like domain leads to a cascade of negative cellular events and motor neuron degeneration. Baicalein is the first drug identified to correct these pathologies by restoring prion-like characteristics to the affected proteins. Our findings suggest that this approach could be vital in treating a wide range of neurodegenerative diseases by stabilizing prion-like folding, normalizing phase condensation, and preventing multiple proteinopathies.