Choosing the optimal mouse model for the study of late-onset spinal muscular atrophy: Why the 4-copy <i>SMN2</i> model offers ideal translational relevance

Spinal muscular atrophy (SMA) comprises a spectrum of clinical severities, yet the pathomechanisms of late-onset forms (Type III) remain insufficiently understood. While severe early-onset SMA has been extensively investigated using existing models, their translational relevance to adult disease is limited. Here, we recommend the 4-copy <i>SMN2</i> mouse (FVB.Cg-<i>Smn1</i>tm1Hung Tg(<i>SMN2</i>)2Hung/J) as the most appropriate model for late-onset SMA. This model exhibits delayed onset, progressive motor dysfunction, and extended survival, enabling the study of chronic neurodegenerative processes, including astrocyte-mediated motor neuron pathology. Its prolonged therapeutic window makes the model suitable for mechanistic and translational investigations of late-onset SMA.