The hereditary spastic paraplegia protein spartin localises to mitochondria
The hereditary spastic paraplegia protein spartin localises to mitochondria
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DOI：
10.1111/j.1471-4159.2006.04008.x
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发表时间：
2006-09-01
影响因子：
4.7
通讯作者：
Byrne, Paula C.
中科院分区：
文献类型：
--
作者：
Lu, JianPing;Rashid, Faiza;Byrne, Paula C.
遗传性痉挛性截瘫描述了一组不同的疾病，其特征是主要影响下肢的进行性截瘫。 Troyer 综合征是一种常染色体隐性遗传性痉挛性截瘫，除了痉挛性截瘫外，患者还伴有构音障碍、远端肌萎缩、发育迟缓和身材矮小。它是由 SPG20 中的移码突变 (1110delA) 引起的，导致斯巴达蛋白（一种功能未知的蛋白质）过早截短。本研究的目的是确定 spartin 的亚细胞定位并研究 1110delA 突变的影响。我们在所有转染的细胞系中观察到斯帕汀的细胞质表达。使用叠加的细胞器标记或免疫细胞化学染色，我们确定斯帕丁定位于线粒体，并且这种定位依赖于 C 末端区域的序列。含有1110delA突变的突变体spartin已经失去了线粒体定位。使用抗α微管蛋白抗体进行的免疫细胞化学染色为斯巴达蛋白与微管的部分共定位提供了证据。荧光共振能量转移分析表明氨基末端的序列对于介导微管相互作用很重要。这项研究提供了斯帕蛋白亚细胞定位的第一个证据，并将其确定为与遗传性痉挛性截瘫有关的第三种线粒体蛋白。我们的结果表明特洛伊综合征可能是由于微管介导的线粒体运输缺陷和/或线粒体功能障碍所致。
Hereditary spastic paraplegia describes a diverse group of disorders characterized by progressive paraparesis primarily affecting lower limbs. In Troyer syndrome, an autosomal recessive form of hereditary spastic paraplegia, patients have dysarthria, distal amyotrophy, developmental delay and short stature in addition to spastic paraparesis. It is caused by a frameshift mutation (1110delA) in SPG20 leading to premature truncation of spartin, a protein with no known function. The objective of this study was to determine the subcellular localization of spartin and investigate the effect of the 1110delA mutation. We observed cytoplasmic expression of spartin in all transfected cell lines. Using superimposed organelle markers or immunocytochemistry staining, we established that spartin localizes to mitochondria and that this localization is dependent on sequences in the C-terminal region. Mutant spartin containing the 1110delA mutation has lost mitochondrial localization. Immunocytochemistry staining using anti-alpha-tubulin antibody provided evidence for partial co-localization of spartin with microtubules. Analysis of fluorescence resonance energy transfer indicated that sequences in the amino terminal are important in mediating microtubule interaction. This study provides the first evidence of spartin subcellular localization and identifies it as the third mitochondrial protein implicated in hereditary spastic paraplegia. Our results suggest that Troyer syndrome may be due to defective microtubule-mediated trafficking of mitochondria and/or mitochondrial dysfunction.