title: 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 StmnKO (Stmn(+/-)) but not homozygous StmnKO (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.
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
authors.forename: Hsin-Lan
authors.initials: HL
authors.lastname: Wen
authors.forename: Chen-Hung
authors.initials: CH
authors.lastname: Ting
authors.forename: Huei-Chun
authors.initials: HC
authors.lastname: Liu
authors.forename: Hung
authors.initials: H
authors.lastname: Li
authors.forename: Sue
authors.initials: S
authors.lastname: Lin-Chao
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D015536:Down-Regulation; D008136:Longevity / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008870:Microtubules / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D050777:Stathmin / Q000235:genetics / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D050777:Stathmin; D055533:Survival of Motor Neuron 1 Protein