Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics
Spastin, the protein mutated in autosomal dominant hereditary spastic paraplegia, is involved in microtubule dynamics
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DOI：
10.1093/hmg/11.2.153
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发表时间：
2002-01-15
影响因子：
3.5
通讯作者：
Rugarli, EI
中科院分区：
文献类型：
--
作者：
Errico, A;Ballabio, A;Rugarli, EI
遗传性痉挛性截瘫（HSP）是由人类最长的轴突皮质脊髓束的特异性变性引起的下肢进行性无力和痉挛的特征。大多数常染色体显性形式的疾病是由于SPG 4基因的突变，该基因编码属于AAA家族的ATP酶spastin。痉挛蛋白的细胞通路及其在引起运动轴突变性中的作用目前尚不清楚。通过在几种细胞类型中表达野生型或ATP酶缺陷型spastin，我们现在表明spastin与微管动态相互作用。Spastin与微管细胞骨架的结合由蛋白质的N-末端区域介导，并通过AAA结构域的ATP酶活性进行调节。所有的错义突变到AAA域，这是以前确定的患者的表达，导致在转染的细胞中的微管的组成性结合，并诱导消失的aster和厚的核周束的形成，这表明痉挛在微管动力学的作用。一致地，野生型spastin促进转染细胞中的微管分解。这些数据表明，spastin可能参与微管动力学类似的高度同源的微管切断蛋白，katanin。由于痉挛素突变，长轴突中微管细胞骨架的精细调节受损，可能是HSP发病机制的基础。
Hereditary spastic paraplegia (HSP) is characterized by progressive weakness and spasticity of the lower limbs, caused by the specific degeneration of the corticospinal tracts, the longest axons in humans. Most cases of the autosomal dominant form of the disease are due to mutations in the SPG4 gene, which encodes spastin, an ATPase belonging to the AAA family. The cellular pathways in which spastin operates and its role in causing degeneration of motor axons are currently unknown. By expressing wild-type or ATPase-defective spastin in several cell types, we now show that spastin interacts dynamically with microtubulles. Spastin association with the microtubule cytoskeleton is mediated by the N-terminal region of the protein, and is regulated through the ATPase activity of the AAA domain. Expression of all the missense mutations into the AAA domain, which were previously identified in patients, leads to constitutive binding to microtubules in transfected cells and induces the disappearance of the aster and the formation of thick perinuclear bundles, suggesting a role of spastin in microtubule dynamics. Consistently, wild-type spastin promotes microtubule disassembly in transfected cells. These data suggest that spastin may be involved in microtubule dynamics similarly to the highly homologous microtubule-severing protein, katanin. Impairment of fine regulation of the microtubule cytoskeleton in long axons, due to spastin mutations, may underlie pathogenesis of HSP.