Salinas Sara, Carazo-Salas Rafael E, Proukakis Christos, Cooper J Mark, Weston Anne E, Schiavo Giampietro, Warner Thomas T
Molecular NeuroPathobiology Laboratories, Cancer Research UK London Research Institute, Lincoln's Inn Fields Laboratories, London, UK.
J Neurochem. 2005 Dec;95(5):1411-20. doi: 10.1111/j.1471-4159.2005.03472.x. Epub 2005 Oct 7.
Hereditary spastic paraplegias (HSPs) are neurodegenerative diseases caused by mutations in more than 20 genes, which lead to progressive spasticity and weakness of the lower limbs. The most frequently mutated gene causing autosomal dominant HSP is SPG4, which encodes spastin, a protein that belongs to the family of ATPases associated with various cellular activities (AAAs). A number of studies have suggested that spastin regulates microtubule dynamics. We have studied the ATPase activity of recombinant human spastin and examined the effect of taxol-stabilized microtubules on this activity. We used spastin translated from the second ATG and provide evidence that this is the physiologically relevant form. We showed that microtubules enhance the ATPase activity of the protein, a property also described for katanin, an AAA of the same spastin subgroup. Furthermore, we demonstrated that human spastin has a microtubule-destabilizing activity and can bundle microtubules in vitro, providing new insights into the molecular pathogenesis of HSP.
遗传性痉挛性截瘫（HSPs）是由20多个基因发生突变引起的神经退行性疾病，这些突变会导致下肢进行性痉挛和无力。导致常染色体显性遗传性痉挛性截瘫最常见的突变基因是SPG4，它编码spastin，一种属于与各种细胞活动相关的ATP酶家族（AAA）的蛋白质。多项研究表明，spastin调节微管动力学。我们研究了重组人spastin的ATP酶活性，并检测了紫杉醇稳定的微管对该活性的影响。我们使用从第二个ATG翻译的spastin，并提供证据表明这是生理相关形式。我们发现微管可增强该蛋白的ATP酶活性，katanin（同一spastin亚组的AAA）也具有此特性。此外，我们证明人spastin具有微管去稳定活性，并且在体外可使微管成束，这为遗传性痉挛性截瘫的分子发病机制提供了新见解。
