Decreased stathmin expression ameliorates neuromuscular defects but fails to prolong survival in a mouse model of spinal muscular atrophy

Abstract Spinal muscular atrophy (SMA), a genetic neurodegenerative disorder, is caused by mutations or deletions in the survival of motor neuron 1 ( SMN1 ) gene that result in SMN deficiency. SMN deficiency impairs microtubule networks in Smn -deficient cells and in SMA-like motor neuron cultures. Microtubule defects can be restored by knockdown of the stathmin gene ( Stmn ), which is upregulated in SMA. However, whether in vivo reduction of stathmin levels could improve the pathology of SMA has not been investigated. Here we generated SMA-like mice in a Stmn knockout (KO) background through a series of genetic crosses. Analyses of motor performance and histology showed that heterozygous Stmn KO ( Stmn +/− ) but not homozygous Stmn KO ( Stmn −/− ) ameliorates some SMA defects, with increased microtubule densities in sciatic axons, improved motor performance, enhanced NMJ maturation, and mitigated neuroinflammation. However, Stmn deletion does not prolong the lifespan of SMA-like mice, suggesting that stathmin dysregulation and microtubule disruption are not a cause but rather a consequence of SMA pathology. This work demonstrates that limiting the amount of stathmin in SMA-like mice is effective in reducing their neuromuscular defects, whereas induced aberrant expression of stathmin in SMA-like animals is detrimental.