Stathmin, a microtubule-destabilizing protein, is dysregulated in spinal muscular atrophy.
Spinal muscular atrophy (SMA), a motor neuron degeneration disorder, is caused by either mutations or deletions of survival motor neuron 1 (SMN1) gene which result in insufficient SMN protein. Here, we describe a potential link between stathmin and microtubule defects in SMA. Stathmin was identified by screening Smn-knockdown NSC34 cells through proteomics analysis. We found that stathmin was aberrantly upregulated in vitro and in vivo, leading to a decreased level of polymerized tubulin, which was correlated with disease severity. Reduced microtubule densities and beta(III)-tubulin levels in distal axons of affected SMA-like mice and an impaired microtubule network in Smn-deficient cells were observed, suggesting an involvement of stathmin in those microtubule defects. Furthermore, knockdown of stathmin restored the microtubule network defects of Smn-deficient cells, promoted axon outgrowth and reduced the defect in mitochondria transport in SMA-like motor neurons. We conclude that aberrant stathmin levels may play a detrimental role in SMA; this finding suggests a novel approach to treating SMA by enhancing microtubule stability.
Wen
Hsin-Lan
HL
Institute of Molecular Biology, Academia Sinica, Taipei 115, Taiwan.
Lin
Yuan-Ta
YT
Ting
Chen-Hung
CH
Lin-Chao
Sue
S
Li
Hung
H
Hsieh-Li
Hsiu Mei
HM
D000818:Animals; D001369:Axons / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002460:Cell Line; D055785:Gene Knockdown Techniques; D007150:Immunohistochemistry; D051379:Mice; D008854:Microscopy, Electron; D008870:Microtubules / Q000378:metabolism* / Q000473:pathology; D009046:Motor Neurons / Q000378:metabolism* / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology; D009841:Oligonucleotides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D050777:Stathmin / Q000378:metabolism*; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*
D009841:Oligonucleotides; C526472:Smn1 protein, mouse; D050777:Stathmin; D055533:Survival of Motor Neuron 1 Protein